JP2024512070A - Indoline as a DDR inhibitor - Google Patents

Abstract

Indoline derivatives as DDR inhibitors The present invention relates to compounds of general formula (I) that inhibit discoidin domain receptors (DDR inhibitors), methods for producing such compounds, pharmaceutical compositions containing them and their therapeutic use.The compounds of the present invention may be useful, for example, in the treatment of many disorders associated with DDR mechanisms.

Description

The present invention relates to compounds that inhibit discoidin domain receptors (DDR inhibitors), methods for producing such compounds, pharmaceutical compositions containing them, and their pharmaceutical uses.

Compounds of the invention may be useful, for example, in the treatment of many disorders associated with DDR mechanisms.

Discoidin domain receptors (DDRs) are type I transmembrane receptor tyrosine kinases (RTKs). The DDR family includes two different members: DDR1 and DDR2.

DDR is unique among other members of the RTK superfamily in that DDR is activated by collagen, whereas other members of the RTK superfamily are primarily activated by soluble peptide-like growth factors. (See Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1:25-34). Furthermore, DDR is an uncommon RTK because it forms stable, non-covalently bound, ligand-independent dimers (Noordeen, N. A. (2006) J. Biol Chem. 281, 22744-22751; see Mihai C. J Mol Biol. 2009; 385:432-445).

The DDR1 subfamily consists of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. All five DDR1 isoforms share extracellular and transmembrane domains but differ in the cytoplasmic region (Valiathan, R. R. (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).

The DDR receptor family has been found to be involved in a range of fibrotic diseases such as pulmonary fibrosis, particularly idiopathic pulmonary fibrosis (IPF). The first evidence for the protective role of DDR1 deletion in pulmonary fibrosis was produced by Dr. Vogel's research group in 2006 (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427 ). The authors showed that DDR1-deficient mice were largely protected from bleomycin (BLM)-induced injury. Furthermore, myofibroblast proliferation and apoptosis were much lower in these animals compared to wild-type controls. The absence of inflammation in knockout mice was confirmed by washed cell counts and cytokine ELISA. These results indicated that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis.

Deficiency or downregulation of DDR2 attenuates bleomycin-induced pulmonary fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al Mol Ther 2016; 24:1734-1744). Zhao et al. showed that DDR2 plays an important role in inducing fibrosis and angiogenesis in the lung, and in particular, DDR2 acts synergistically with transforming growth factor (TGF)-β to differentiate myofibroblasts. was shown to induce Furthermore, we showed that treating injured mice with a specific siRNA against DDR2 had a therapeutic effect on pulmonary fibrosis. In a second publication, Jia et al. showed that DDR2-deficient mice are protected from bleomycin-induced pulmonary fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018;59:295-305). Furthermore, fibroblasts lacking DDR2 were significantly more prone to apoptosis than wild-type fibroblasts, supporting the paradigm that fibroblast resistance to apoptosis is important for fibrosis progression. ing.

Several compounds have been described in the literature as DDR1 or DDR2 antagonists.

WO2016064970 (Guangzhou) describes isoquinoline derivatives as DDR1 inhibitors useful as therapeutic agents for the prevention and treatment of inflammation, liver fibrosis, renal fibrosis, pulmonary fibrosis, skin scarring, atherosclerosis and cancer. Disclosed.

Of note, inhibiting DDR receptors may be useful in the treatment of fibrosis and diseases, disorders and conditions caused by fibrosis, and furthermore antagonizes both receptors DDR1 and DDR2. This may be particularly useful in the treatment of the diseases, disorders and conditions mentioned above.

Over the past few years, several efforts have been made to develop novel DDR1 and DDR2 receptor inhibitors useful in the treatment of several diseases, and some of these compounds have also shown efficacy in humans. There is.

Despite the prior art cited above, good activity in the lungs, good lung retention, and low metabolic stability, to be administered by the inhalation route and to minimize systemic exposure and associated safety issues. The receptors DDR1 and DDR1 are useful in the treatment of diseases or conditions associated with dysregulation of DDR receptors in the respiratory area, especially in idiopathic pulmonary fibrosis (IPF), characterized by a favorable inhalation profile corresponding to gender. There remains the possibility of developing both selective inhibitors of DDR2.

In this direction, we have surprisingly solved the problem of providing inhibitors for receptors DDR1 and DDR2 for administration by inhalation and selective inhibitors of receptors DDR1 and DDR2 for other human protein kinases. We have found a new series of compounds of general formula (I), as reported herein below, which are active as Such compounds exhibit high efficacy, good inhalation profile, low metabolic stability, low systemic exposure, improved safety and tolerability.

In a first aspect, the invention provides formula (I):
[In the formula,
R is H or -(C ₁ -C ₄ )alkyl;
L is selected from the group consisting of _-CH2- and -C(O)-;
L ₁ is selected from the group consisting of -C(O)NH- and -NHC(O)-;
Hy may be optionally substituted by one or more groups selected from -(C ₁ -C ₄ )alkyl, heterocycloalkyl and -(C ₁ -C ₄ )alkylene-NR _A R _B is a bicyclic heteroaryl, or
Hy is a bicyclic semisaturated heteroaryl;
R _A is H or -(C ₁ -C ₄ )alkyl;
R _B is H or -(C ₁ -C ₄ )alkyl;
R ₁ is selected from the group consisting of Het and X, where
-Het is -(C ₁ -C ₄ )alkyl, -(C ₁ -C ₄ ) haloalkyl, -(C ₁ -C ₄ )alkylene-heterocycloalkyl-NR _A R _B , -(C ₁ -C _{4 )} ) _{alkylene - NR} optionally substituted by -C ₄ )alkyl;
-X is the expression:
(wherein R ₂ is selected from the group consisting of -O(C ₁ -C ₄ )haloalkyl, halogen atom and -(C ₁ -C ₄ )haloalkyl;
R ₃ is H or -O(C ₁ -C ₄ )alkyl, -C(O)NH-(C ₁ -C ₄ )alkylene-NR _A R _B , -C(O)-heterocyclo alkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C ₁ -C ₄ )alkyl, -O-heterocycloalkyl; , said heterocycloalkyl is one or more of -(C ₁ -C ₄ )alkyl, -O(C ₁ -C ₄ )alkylene-heterocycloalkyl, -(C ₁ -C ₄ )alkylene-NR _A R _B , heteroaryl optionally substituted by one or more -(C ₁ -C ₄ )alkyl, and optionally substituted by monocyclic heterocycloalkyl-(C ₁ -C ₄ )alkylene- wherein said heterocycloalkyl may be optionally substituted by one or more groups selected from -(C ₁ -C ₄ )alkyl and -NR _A R _B )
]
and pharmaceutically acceptable salts thereof.

In a second aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients.

In a third aspect, the invention provides a compound of formula (I) and a pharmaceutically acceptable salt thereof, or a compound of formula (I) and a pharmaceutically acceptable salt thereof, for use as a medicament. Regarding the composition.

In a further aspect, the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, or compounds of formula (I) for use in the prevention and/or treatment of diseases, disorders or conditions associated with dysregulation of DDR. The present invention relates to a pharmaceutical composition comprising a compound of I) and a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the prevention and/or treatment of fibrosis and/or diseases, disorders or conditions in which fibrosis is involved; or to a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable salt thereof.

In a further aspect, the invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, or compounds of formula (I) for use in the prevention and/or treatment of idiopathic pulmonary fibrosis (IPF). and a pharmaceutical composition comprising the pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Definitions Unless otherwise specified, the compounds of formula (I) of the present invention are also intended to include stereoisomers, tautomers or pharmaceutically acceptable salts or solvates thereof. There is.

Unless otherwise specified, the compounds of formula (I) of the present invention include formula (IA), formula (IA'), formula (IA''), formula (IAa), formula (IAa'), formula (IAa'S), Formula (IAa''), Formula (IAa''S), Formula (IAb), Formula (IAb'), Formula (IAb''), Formula (IB), Formula (IBa), Formula (IBa'), Formula Also intended to include compounds of formula (IBa'S), formula (IBa''), formula (IBa''S), formula (IBb), formula (IBb'), formula (IBb'').

As used herein, the term "pharmaceutically acceptable salt" refers to any free acid or basic group (if present) that is conventionally intended to be pharmaceutically acceptable. means a derivative of a compound of formula (I) in which the parent compound has been suitably modified by converting it into the corresponding addition salt with a base or acid.

Suitable examples of said salts therefore include mineral acid addition salts or organic acid addition salts of basic residues such as amino groups, as well as mineral acid addition salts or organic basic addition salts of acidic residues such as carboxyl groups. be.

Cations of inorganic bases which can be suitably used for the preparation of the salts include alkali metal or alkaline earth metal ions such as potassium, sodium, calcium or magnesium.

Salts obtained by reacting the main compound that functions as a base with an inorganic or organic acid include, for example, hydrochloride, hydrobromide, sulfate, phosphate, methanesulfonate. , camphor sulfonate, acetate, oxalate, maleate, fumarate, succinate and citrate.

The term "solvate" refers to a physical association of a compound of the invention with one or more solvent molecules, whether organic or inorganic. This physical association also includes hydrogen bonds. In certain instances, solvates are isolatable, eg, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. Solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules.

The term "stereoisomer" refers to isomers of the same structure that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.

The term "enantiomer" means one of a pair of molecular species that are mirror images of each other and are not superimposable.

The term "diastereomer" means a stereoisomer that is not a mirror image.

The term "racemate" or "racemic mixture" means a composition consisting of equimolar amounts of two enantiomeric species and without optical activity.

The term "tautomer" refers to each of two or more isomers of a compound that exist together in equilibrium and are readily interchangeable by transfer of atoms or groups within the molecule.

The term "halogen" or "halogen atom" or "halo" as used herein includes fluorine, chlorine, bromine and iodine atoms.

The term "(C _x -C _y )alkyl", where x and y are integers, means a straight or branched alkyl group having x to y carbon atoms. Thus, for example, when x is 1 and y is 6, the term includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and t-butyl.

The term "O(C _x -C _y )alkyl" (where x and y are integers) means "(C _x -C _y )alkyl" group, such as ethoxy.

The term "(C _x -C _y )haloalkyl" (where x and y are integers) means that one or more hydrogen atoms may be the same or different, and one or more halogen atoms may be the same or different. means an "(C _x -C _y )alkyl" group as defined above, which is replaced with . Examples of said "(C _x -C _y )haloalkyl" groups include halogenated alkyl groups and polyhalogenated alkyl groups, and fully halogenated alkyl groups in which all hydrogen atoms are replaced with halogen atoms, such as trifluoro Examples include methyl.

The term "O(C _x -C _y ) haloalkyl" (where x and y are integers) means "(C _x -C _y ) haloalkyl” group.

Thus, examples of the aforementioned "O(C _x -C _y ) haloalkyl" groups include halogenated O-alkyl groups, poly-halogenated O-alkyl groups, and fully halogenated groups in which all hydrogen atoms are replaced with halogen atoms. O-alkyl groups, such as trifluoromethoxy.

The term "aryl" means a monocyclic carbocyclic ring system having six ring atoms in which the ring is aromatic. Examples of suitable aryl monocyclic ring systems include, for example, phenyl.

The term "heteroaryl" means a monocyclic or bicyclic aromatic group containing one or more heteroatoms selected from S, N, and O, wherein two such monocyclic rings or in which one such monocyclic ring and one monocyclic aryl ring are fused through a common bond. Examples of suitable heteroaryls include, for example (imidazo[1,2-a]pyridinyl), 1H-pyrrolo[2,3-b]pyridyl, 1H-pyrazolo[3,4-b]pyridinyl, benzo[d ]thiazolyl, 1H-indazolyl, 1H-benzo[d]imidazolyl, isoquinolinyl, imidazo[1,2-a]pyrazinyl, 1H-pyrazolo[3,4-b]pyridinyl, 1H-benzo[d]imidazolyl; 1H-pyrrolo [2,3-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, pyrazolo[1,5-a]pyrazinyl, pyrazolyl, pyridinyl, isoxazolyl, and pyrimidinyl.

The term "semisaturated heteroaryl" means a bicyclic group containing one or more heteroatoms selected from S, N, and O, and one or more monocyclic heterocycloalkyl rings. Includes monocyclic heteroaryls fused to. Examples of suitable semisaturated heteroaryls include, for example, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl.

The term "heterocycloalkyl" means a saturated or partially unsaturated monocyclic or bicyclic ring of 3 to 12 ring atoms containing one or more heteroatoms selected from N, S or O. means a ring system of the formula eg piperazinyl, morpholinyl, pyrrolidinyl, piperidinyl.

The term "heterocycloalkyl-(C _x -C _y )alkylene" means a heterocycloalkyl bonded to a straight-chain or branched (C _x -C _y )alkylene group having x to y carbon atoms, such as ( 4-Methylpiperazin-1-yl)methyl, morpholinomethyl, pyrrolidin-1-ylmethyl.

As used in the structural formulas herein
A wavy line or a bond pointing to a wavy line, such as, indicates a bond that is the point of attachment of the moiety or substituent to the core or backbone structure.

When referring to substituents, a dash (“-”) that is not between two letters, words, or symbols is meant to represent the point of attachment of such substituents.

Carbonyl groups are preferably designated herein as -C(O)-, as an alternative to other common expressions such as -CO-, -(CO)- or -C(=O)-.

When referring to the group -C(O)NH- or -NHC(O)- in L ₁ of formula (I), the left dash (“-”) of that group indicates the bond between that group and the indoline core. , and the right dash (“-”) of that group is the bond between that group and the R ₁ group. Thus, when referring to -C(O)NH- in L ₁ of formula (I), the carbon is attached to the indoline core and the nitrogen is attached to the R ₁ group. When referring to -NHC(O)- in L ₁ of formula (I), the nitrogen is attached to the indoline core and the carbon is attached to the R ₁ group.

Whenever a basic amino group is present in a compound of formula (I), it can be chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate. selected from acid salts, acetates, citrates, fumarates, tartrates, oxalates, succinates, benzoates, p-toluenesulfonates, pamoates and naphthalene disulfonates , physiologically acceptable anions may be present. Similarly, in the presence of acidic groups, corresponding physiological cationic salts may also be present, including, for example, alkali metal ions or alkaline earth metal ions.

The term "half maximal inhibitory concentration" (IC50) refers to the concentration of a particular compound or molecule required to inhibit a biological process by 50% in vitro.

The term "Ki" refers to the dissociation constant of an enzyme-inhibitor complex and is expressed in molar units. It is a measure of the binding affinity between an inhibitor and the DDR1 or DDR2 receptor.

The present invention refers to novel compounds that differ from the structures disclosed in the art for at least the common new core scaffold. Indeed, the present invention provides that the indoline nitrogen is attached to the bicyclic heteroaryl ring Hy via the linker _-CH2- or -C(O)-, as shown in the general formula (I) described in detail below. The present invention relates to compounds that are indoline derivatives having inhibitory activity on receptors DDR1 and DDR2.

As detailed in the experimental section below, compounds of formula (I) of the invention are capable of acting as antagonists of both DDR1 and DDR2 receptors in a substantial and effective manner. In particular, Table 7 below shows that for compounds of the invention, both the affinity for either DDR1 and DDR2 receptors and the inhibitory activity for either DDR1 and DDR2 receptors are determined by binding (expressed as Ki) and Each is shown to be less than about 80 nM in cell-based assays (expressed as IC50). This confirms that compounds of formula (I) are able to inhibit two isoforms of DDR receptors that are primarily involved in fibrosis and diseases caused by fibrosis. Compounds of formula (I) can therefore be used in the treatment of fibrosis, particularly pulmonary fibrosis, where DDR1 and DDR2 are involved.

Guangzhou discloses tetrahydroisoquinoline-7-carboxamide as a selective DDR1 inhibitor.

Remarkably, in the compounds of formula (I) according to the invention, the presence of at least the indoline moiety and the spacer -CH2- or -C(O)- between the nitrogen atom of the pyrrolidine and the heteroaryl group Hy , unexpectedly and significantly determines the high affinity for both DDR1 and DDR2 receptors and the appropriate inhibitory activity for DDR1 and even DDR2 receptors in cellular assays.

Furthermore, as shown in the experimental part, comparative examples, and in particular Table 8, contrary to the compounds of Examples C1 and C2, which feature a _-CH2 -C(O)- linker between the indoline ring and the Hy group. , showed that the presence of a -CH2- or -C(O)- linker at that position in the compounds of the invention unexpectedly and significantly determines an associated increase in inhibitory activity towards both DDR1 and DDR2 receptors. ing.

In particular, a direct comparison of Example C1 of the present invention with Examples 14 and 11, which differ only in the linker between the indoline group and the Hy, shows that -C(O)- and We highlight that the respective presence of the -CH2- linker determines an unexpected and significant increase in activity towards both DDR1 and DDR2 receptors. Similarly, a direct comparison of the compound of Example C2 of the invention and the compound of Example 16, which differ only in the linker between the indoline group and the Hy, shows that the presence of the -C(O)- linker It is emphasized that the body determines an unexpected and significant increase in activity for both.

Advantageously, the compounds of the present invention have very high potency and can be administered to humans at lower doses than prior art compounds, resulting in lower doses of the drug than can occur when administering high doses of the drug. This can reduce the number of adverse events that can occur.

The compounds of the invention, in addition to being significantly potent with respect to inhibitory activity against both receptors DDR1 and DDR2, are selective inhibitors of the DDR1 and DDR2 receptors with respect to other human protein kinases, and are effective in the pulmonary compartment. It has a good inhalation profile that allows it to act effectively, and at the same time low metabolic stability that allows it to minimize the drawbacks associated with systemic exposure, such as safety and tolerability issues. It is characterized by.

The compounds of the invention are therefore useful in the treatment of fibrosis, particularly idiopathic pulmonary fibrosis, are administered by the inhalation route, and correspond to good pulmonary activity, good pulmonary retention, and low metabolic stability. It is particularly appreciated by those skilled in the art in view of being a suitable and effective compound, characterized by a good inhalation profile, minimizing systemic exposure and associated safety issues.

Therefore, in one aspect, the present invention provides general formula (I):
[In the formula,
R is H or -(C ₁ -C ₄ )alkyl;
L is selected from the group consisting of _-CH2- and -C(O)-;
L ₁ is selected from the group consisting of -C(O)NH- and -NHC(O)-;
Hy may be optionally substituted by one or more groups selected from -(C ₁ -C ₄ )alkyl, heterocycloalkyl and -(C ₁ -C ₄ )alkylene-NR _A R _B is a bicyclic heteroaryl, or Hy is a bicyclic semisaturated heteroaryl;
R _A is H or -(C ₁ -C ₄ )alkyl;
R _B is H or -(C ₁ -C ₄ )alkyl;
R ₁ is selected from the group consisting of Het and X, where
-Het is -(C ₁ -C ₄ )alkyl, -(C ₁ -C ₄ ) haloalkyl, -(C ₁ -C ₄ )alkylene-heterocycloalkyl-NR _A R _B , -(C ₁ -C _{4 )} ) _{alkylene - NR} optionally substituted by -C ₄ )alkyl, and
-X is the expression:
(wherein R ₂ is selected from the group consisting of -O(C ₁ -C ₄ )haloalkyl, halogen atom and -(C ₁ -C ₄ )haloalkyl;
R ₃ is H or -O(C ₁ -C ₄ )alkyl, -C(O)NH-(C ₁ -C ₄ )alkylene-NR _A R _B , -C(O)-heterocyclo alkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C ₁ -C ₄ )alkyl, -O-heterocycloalkyl; , said heterocycloalkyl is one or more of -(C ₁ -C ₄ )alkyl, -O(C ₁ -C ₄ )alkylene-heterocycloalkyl, -(C ₁ -C ₄ )alkylene-NR _A R _B , heteroaryl optionally substituted by one or more -(C ₁ -C ₄ )alkyl, and optionally substituted by monocyclic heterocycloalkyl-(C ₁ -C ₄ )alkylene- wherein said heterocycloalkyl may be optionally substituted by one or more groups selected from -(C ₁ -C ₄ )alkyl and -NR _A R _B )
]
or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention relates to compounds of general formula (I) in which Hy is bicyclic heteroaryl, wherein the heteroatoms are represented by one or more N atoms. .

In another preferred embodiment, the present invention provides compounds of formula (I) wherein Hy is optionally substituted by one or more groups selected from methyl, (dimethylamino)methyl and morpholinyl. or Hy is semisaturated heteroaryl.

In another preferred embodiment, the present invention provides compounds of formula (I) in which Hy is (imidazo[1,2-a]pyridin-3-yl), 1H-pyrrolo[2,3-b]pyridine- 5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, benzo[d]thiazol-6-yl, 1H-indazol-5-yl, 1H-benzo[d]imidazol-5-yl, Isoquinolin-7-yl, imidazo[1,2-a]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrazolo[3,4-b] Pyridin-5-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 1H-benzo[d]imidazol-5-yl, 1H-benzo[d]imidazol-5-yl, 3-(( dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 2,3-dihydro-1H-pyrrolo[2,3- b]pyridin-5-yl, 3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyridin-3-yl and pyrazolo[1,5-a] selected from the group consisting of pyrimidin-6-yl].

In a further preferred embodiment, the present invention provides a compound of formula (I) in which Het is 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 2-((3-(dimethylamino) )pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6-(trifluoromethyl)-6-(trifluoromethyl)pyridin-3-yl, Fluoromethyl)pyridin-4-yl, ((4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 3-(tert-butyl)isoxazol-5-yl, 5 -(tert-butyl)isoxazol-3-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-(trifluoromethyl)pyrimidin-4-yl and 5-(1, selected from the group consisting of 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl.

In another particularly preferred embodiment, the present invention provides compounds of the formula (I) in which X is 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl, 3- (4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-methoxy-3 -(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl, 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 5-(1,1,1-trifluoro-2 -Methylpropan-2-yl)isoxazol-3-yl, 3-fluoro-5-(trifluoromethoxy)phenyl, 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl, 4 -((dimethylamino)methyl)-3-(trifluoromethyl)phenyl, 3-(morpholinomethyl)-5-(trifluoromethyl)phenyl, 3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl) ) phenyl, 3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl, 3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl; 3-(2 -morpholinoethoxy)-5-(trifluoromethyl)phenyl, 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl, 4-((dimethylamino)methyl)-3 -(trifluoromethyl)phenyl, 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl, 3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl) Fluoromethyl)phenyl, 3-((2-(dimethylamino)ethyl)carbamoyl)-5-(trifluoromethyl)phenyl, 3-(4-methylpiperazine-1-carbonyl)-5-(trifluoromethyl)phenyl and 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl].

In a particularly preferred embodiment, the present invention provides compounds of the general formula (I) in which L ₁ is -C(O)NH-, wherein the compounds of the formula (IA):
It relates to a compound of the formula: wherein R, L, Hy and R ₁ are as defined above.

In another preferred embodiment, the present invention provides a compound of formula (IA), wherein L is -C(O)-, comprising a compound of formula (IA'):
Relating to compounds of the formula: wherein R, Hy and R ₁ are as defined above.

In a further preferred embodiment, the present invention provides compounds of the formula (IA') [wherein R ₁ is 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl and 3- (4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl, and Hy is imidazo[1,2-a]pyridin-3-yl, imidazo[ 1,2-a]pyrazin-3-yl and 1H-pyrazolo[3,4-b]pyridin-5-yl].

According to a preferred embodiment, the present invention relates to at least one compound of formula (IA') shown in Table 1 below and a pharmaceutically acceptable salt thereof. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

In another preferred embodiment, the present invention provides compounds of formula (IA), wherein L is _-CH2- , comprising formula (IA''):
Relating to compounds of the formula: wherein R, Hy and R ₁ are as defined above.

In a further preferred embodiment, the present invention provides a compound of the formula (IA''), wherein R ₁ is 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl, 3 -(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl), 3-(trifluoromethyl)phenyl, 3-fluoro-5-(trifluoromethyl)phenyl, 4-methoxy -3-(trifluoromethyl)phenyl, 3-(trifluoromethoxy)phenyl; 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 5-(1,1,1-trifluoro -2-methylpropan-2-yl)isoxazol-3-yl, 3-fluoro-5-(trifluoromethoxy)phenyl, 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl , 4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl, 3-(morpholinomethyl)-5-(trifluoromethyl)phenyl, 3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl Fluoromethyl)phenyl, 3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl, 3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl; 3- (2-morpholinoethoxy)-5-(trifluoromethyl)phenyl, 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl, 4-((dimethylamino)methyl) -3-(trifluoromethyl)phenyl, 4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl, 3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5- (trifluoromethyl)phenyl, 3-((2-(dimethylamino)ethyl)carbamoyl)-5-(trifluoromethyl)phenyl, 3-(4-methylpiperazine-1-carbonyl)-5-(trifluoromethyl) ) phenyl, 2-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2- ((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl, 4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 3-(tert -butyl)isoxazol-5-yl, 5-(tert-butyl)isoxazol-3-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-(trifluoromethyl)pyrimidine -4-yl and 4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl, and Hy is imidazo[1,2-a]pyridine -3-yl, 1H-pyrrolo[2,3-b]pyridine, 1H-indazol-5-yl, 1H-benzo[d]imidazol-5-yl, isoquinolin-7-yl, imidazo[1,2-a ]pyrazin-3-yl, 1H-pyrazolo[3,4-b]pyridin-5-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-((dimethylamino) methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl, pyrazolo[1,5-a]pyrimidin-6-yl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine -5-yl, 3-morpholino-1H-pyrazolo[3,4-b]pyridin-5-yl, pyrazolo[1,5-a]pyrazin-3-yl and 1H-benzo[d]imidazol-5-yl selected from the group consisting of].

According to a preferred embodiment, the invention relates to at least one of the compounds of formula (IA'') listed in Table 2 below and pharmaceutically acceptable salts thereof. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

In a particularly preferred embodiment, the present invention provides a compound of the general formula (IA) [wherein R ₁ is an X group:
A compound having the formula (IAa):
It relates to a compound of the formula: [wherein R, L, Hy, _R2 and _R3 are as defined above].

In a particularly preferred embodiment, the present invention provides a compound of formula (IAa), wherein L is -C(O)-, comprising a compound of formula (IAa'):
Relating to compounds of the formula: [wherein R, Hy, _R2 and _R3 are as defined above].

In another particularly preferred embodiment, the present invention provides a method according to the general formula (I) in which L is -C(O)-, L ₁ is -C(O)NH- and R ₁ is :
is a compound of the formula (IAa'S):
Relating to compounds of the formula: [wherein R, Hy, _R2 and _R3 are as defined above].

In a further particularly preferred embodiment, the present invention provides compounds of the general formula (IAa), in which L is _-CH2- , comprising the formula (IAa''):
It relates to a compound represented by the formula: [wherein R, Hy, R ₁ , R ₂ and R ₃ are as defined above].

In a further preferred embodiment, the present invention provides a compound of the general formula (I) [wherein L is _-CH2- , _L1 is -C(O)NH-, and _R1 is X':
is a compound with the formula (IAa''S):
Relating to compounds of the formula: [wherein R, Hy, _R2 and _R3 are as defined above].

In a further particularly preferred embodiment, the invention provides compounds of the general formula (I) in which L ₁ is -C(O)NH- and R ₁ is Het, wherein the compounds of the formula (IAb) :
It relates to a compound of the formula: wherein R, L, Hy and Het are as defined above.

In a further preferred embodiment, the present invention provides a compound of the general formula (IAb), in which L is -C(O)-, comprising the formula (IAb'):
Relating to a compound of the formula: wherein R, Hy and Het are as defined above.

In another particularly preferred embodiment, the invention provides compounds of the general formula (IAb), in which L is _-CH2- , comprising the formula (IAb''):
Relating to a compound of the formula: wherein R, Hy and Het are as defined above.

In a further preferred embodiment, the present invention provides a compound of the formula (IAb'') [wherein Het is 3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl, 2-((3-( dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 5-(trifluoromethyl)pyridin-3-yl, 2-((dimethylamino)methyl)-6- (trifluoromethyl)pyridin-4-yl, 4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl, 3-(tert-butyl)isoxazol-5-yl, 5 -(tert-butyl)isoxazol-3-yl, 5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl, 6-(trifluoromethyl)pyrimidin-4-yl and 5-(1, 1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl).

In another preferred embodiment, the present invention provides a compound of the formula (IAb'') [wherein Hy is 1H-pyrazolo[3,4-b]pyridin-5-yl, imidazo[1,2-a]pyridine- 3-yl, 3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl and imidazo[1,2-a]pyrazin-3-yl].

According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (IAb'') listed in Table 3 below and pharmaceutically acceptable salts thereof. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

In another preferred embodiment, the present invention provides compounds of the general formula (I), wherein L ₁ is -NHC(O)-, wherein the compounds of the formula (IB):
It relates to a compound of the formula: wherein R, L, Hy and R ₁ are as defined above.

According to a preferred embodiment, the invention relates to at least one of the compounds of formula (IB) listed in Table 4 below and pharmaceutically acceptable salts thereof. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

In a particularly preferred embodiment, the present invention provides a compound of the general formula (I) [wherein L ₁ is -NHC(O)- and R ₁ is an X group:
is a compound of the formula (IBa):
It relates to a compound of the formula: [wherein R, L, Hy, _R2 and _R3 are as defined above].

In a further preferred embodiment, the present invention provides compounds of the general formula (IBa), in which L is -C(O)-, comprising the formula (IBa'):
Relating to compounds of the formula: [wherein R, Hy, _R2 and _R3 are as defined above].

In another preferred embodiment, the present invention provides a compound of the general formula (I) [wherein L ₁ is -NHC(O)-, L is -C(O)-, and R ₁ is X':
is a compound of the formula (IBa'S):
Relating to compounds of the formula: [wherein R, Hy, _R2 and _R3 are as defined above].

In a further preferred embodiment, the present invention provides compounds of the formula (IBa'S) [wherein R ₂ is trifluoromethyl; R ₃ is 4-methyl-1H-imidazol-1-yl and (4-methylpiperazine- and Hy is 1H-pyrazolo[3,4-b]pyridin-5-yl, imidazo[1,2-a]pyridin-3-yl and 1-(imidazo[1, 2-a] pyrazin-3-yl].

According to a preferred embodiment, the invention relates to at least one of the compounds of formula (IBa'S) listed in Table 5 below and pharmaceutically acceptable salts thereof. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

In another particularly preferred embodiment, the invention provides compounds of the formula (IBa), in which L is _-CH2- , comprising the formula (IBa''):
Relating to compounds of the formula: [wherein R, Hy, _R2 and _R3 are as defined above].

In a particularly preferred embodiment, the present invention provides a compound of the general formula (I) [wherein L ₁ is -NHC(O)-, L is -CH ₂ - and R ₁ is X':
is a compound with the formula (IBa''S):
It relates to a compound of the formula: [wherein R, Hy, R ₂ and R ₃ are as defined above].

In a further preferred embodiment, the present invention provides a method of formula (IBa''S) wherein R ₂ is trifluoromethyl; R ₃ is H or 4-methyl-1H-imidazole-1 and Hy is selected from the group consisting of -yl and 4-(methylpiperazin-1-yl)methyl; and Hy is imidazo[1,2-a]pyridin-3-yl; benzo[d]thiazol-6-yl; imidazo[1,2-a]pyrazin-3-yl and 1H-pyrazolo[3,4-b]pyridin-5-yl].

According to a preferred embodiment, the present invention relates to at least one of the compounds of formula (IBa''S) listed in Table 6 below and pharmaceutically acceptable salts thereof. These compounds are particularly active against the receptors DDR1 and DDR2, as shown in Table 7.

In a particularly preferred embodiment, the present invention provides compounds of the general formula (I), in which L ₁ is -NHC(O)- and R ₁ is Het, wherein the compounds of the formula (IBb):
Regarding the compound represented by.

In another preferred embodiment, the present invention provides compounds of the general formula (IBb), in which L is -C(O)-, comprising the formula (IBb'):
Relating to a compound of the formula: wherein R, Hy and Het are as defined above.

In another preferred embodiment, the present invention provides compounds of the general formula (IBb), in which L is _-CH2- , comprising the formula (IBb''):
Relating to a compound of the formula: wherein R, Hy and Het are as defined above.

It is clearly understood that any compound of the invention may be encompassed by more than one general formula. For example, without limitation, a compound may be encompassed by both formula (IA'') and formula (IAb''), in both of which L is CH ₂ and L ₁ is -C (O)NH-.

Compounds of the invention (including all compounds listed above herein) can be prepared using the following general methods and procedures, or using slightly modified processes readily available to those skilled in the art. It can be prepared from readily available starting materials. Although particular embodiments of the invention may be shown or described herein, those skilled in the art will appreciate that all implementations or embodiments of the invention can be implemented using the methods described herein. , or other known methods, reagents and starting materials. Where typical or preferred process conditions (ie, reaction temperature, time, molar ratios of reactants, solvent, pressure, etc.) are given, other process conditions can also be used, unless otherwise indicated. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art by routine optimization procedures.

In some cases, commonly known protective groups (PGs) can also be employed when necessary to mask or protect sensitive or reactive moieties according to general principles of chemistry. organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts).

The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both receptors DDR1 and DDR2. Advantageously, inhibition of receptors DDR1 and DDR2 may result in effective treatment of diseases or conditions in which DDR receptors are implicated.

In this regard, it has now been found that the compounds of formula (I) of the present invention have an inhibitory potency expressed as inhibition constant Ki for DDR1 and DDR2 lower than 80 nM, as shown in the present experimental part. . Preferably, compounds of the invention have a Ki lower than 50 nM towards DDR1 and DDR2. More preferably, the compounds of the invention have a Ki lower than 25 nM towards DDR1 and DDR2.

Furthermore, the compounds of formula (I) of the present invention have been shown to be effective at binding (expressed as Ki) and cell-based assays (expressed as IC50) at the DDR1 and DD2 receptors, as shown in the present experimental part. Both the affinity for and the inhibitory activity for either DDR1 and DDR2 receptors were found to be less than about 80 nM each. Preferably, compounds of the invention have a Ki and/or IC50 for DDR1 and DDR2 receptors of less than 50 nM. More preferably, the compounds of the invention have a Ki and/or IC50 for DDR1 and DDR2 receptors of less than 25 nM.

In one aspect, the present invention relates to a compound of formula (I) according to any of the embodiments disclosed above for use as a medicament.

In a preferred embodiment, the present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof for use in the treatment of diseases, disorders or conditions associated with dysregulation of DDR.

In another aspect, the invention relates to the use of a compound of formula (I) as described above in the preparation of a medicament for the treatment of disorders associated with dysregulation of the DDR.

In a preferred embodiment, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention and/or treatment of diseases, disorders or conditions associated with DDR receptor mechanisms. In one embodiment, the present invention relates to compounds of formula (I) useful for the prevention and/or treatment of fibrosis and/or diseases, disorders or conditions in which fibrosis is involved.

As used herein, the term "fibrosis" or "fibrotic disorder" refers to a condition associated with abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment. , including, but not limited to, fibrosis of individual organs or tissues such as the heart, kidneys, liver, joints, lungs, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal, and gastrointestinal tract.

Preferably, the compounds of formula (I) above are used to treat pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. It is useful for the treatment and/or prevention of fibrosis such as.

More preferably, the compound of formula (I) above is for the treatment of idiopathic pulmonary fibrosis (IPF).

In one aspect, the invention also provides a method for preventing and/or treating disorders associated with DDR receptor mechanisms, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as described above. Relating to a method comprising:

In a further aspect, the invention relates to the use of a compound of formula (I) as described above for treating disorders associated with DDR receptor mechanisms.

In another aspect, the invention relates to the use of a compound of formula (I) as described above in the preparation of a medicament for treating disorders associated with DDR receptor mechanisms.

In a further aspect, the present invention provides a method for preventing and/or treating a disorder or condition associated with dysregulation of DDR receptors 1 and 2, comprising administering to a patient in need thereof a therapeutically effective amount of the above formula ( A method comprising administering a compound of I).

In a further aspect, the invention relates to the use of a compound of formula (I) as described above for treating a disease, disorder or condition associated with dysregulation of DDR receptors 1 and 2.

As used herein, a "safe and effective amount" with respect to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent is a "safe and effective amount" for treating a patient's condition. It means an amount of compound that is sufficient, but low enough to avoid serious side effects, which can nevertheless be determined routinely by one of ordinary skill in the art.

The compounds of formula (I) may be administered in a single dose or according to a regimen in which multiple doses are administered at various time intervals over a given period of time. Typical daily doses may vary depending on the route of administration chosen.

The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) according to any of its embodiments, together with at least one or more pharmaceutically acceptable carriers or excipients.

In one embodiment, the present invention is combined with one or more pharmaceutically acceptable carriers or excipients, such as those described in Remington's Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A. PHARMACEUTICAL COMPOSITIONS OF COMPOUNDS OF FORMULA (I) IN ADDITION.

The compounds of the present invention and their pharmaceutical compositions may be administered depending on the needs of the patient, such as oral administration, nasal administration, parenteral administration (subcutaneous administration, intravenous administration, intramuscular administration, intrasternal administration, and injection) and inhalation.

Preferably, the compounds of the invention are administered orally or by inhalation.

In one preferred embodiment, the pharmaceutical compositions comprising a compound of formula (I) are solid oral dosage forms such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.

In one embodiment, the pharmaceutical composition comprising a compound of formula (I) is a tablet.

The compounds of the present invention can be carried out alone or in various pharmaceutically acceptable carriers, diluents (sucrose, mannitol, lactose, starch, etc.) and suspending agents, solubilizing agents, buffers, binders, disintegrants, preservatives, etc. It can be administered in combination with known excipients, including agents, colorants, flavoring agents, lubricants, and the like.

In further embodiments, pharmaceutical compositions comprising compounds of formula (I) are liquid oral dosage forms such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups and elixirs. Such liquid dosage forms may also contain suitable known inert diluents such as water, and suitable known excipients such as preservatives, wetting agents, sweetening agents, flavoring agents, and compounds of the invention. It may contain agents for emulsifying and/or suspending.

In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is an inhalable preparation, such as an inhalable powder, a propellant-containing metered aerosol, or a propellant-free inhalable formulation.

When administered as a dry powder, single-dose or multi-dose inhalers known from the prior art can be utilized. In that case, the powder can be filled into gelatin, plastic or other capsules, cartridges or blister packs or reservoirs.

Diluents or carriers that are chemically inert to the compounds of the invention, such as lactose or other additives suitable for improving the respirable fraction, may be added to the powdered compounds of the invention. .

Inhalable aerosols containing propellant gases such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. Propellant-driven formulations may contain other ingredients such as cosolvents, stabilizers, and optionally other excipients.

The propellant-free inhalable preparations containing the compounds of the invention may be in the form of a solution or suspension in an aqueous, alcoholic or hydroalcoholic medium, using any jet nebulizer or It may be delivered by an ultrasonic nebulizer or a soft mist nebulizer.

The compounds of the invention can be administered alone or in combination with other pharmaceutically active ingredients.

The dosage of the compounds of the invention will depend on a variety of factors including, among other things, the particular disease being treated, the severity of the symptoms, the route of administration, and the like.

The invention is also directed to devices containing a pharmaceutical composition comprising a compound of formula (I) according to the invention in the form of a single-dose or multi-dose dry powder inhaler or metered dose inhaler.

All preferred groups or embodiments mentioned above for the compounds of formula (I) may be combined with one another and apply mutatis mutandis.

Compounds of the invention (including all compounds listed above herein) can be prepared using the following general methods and procedures, or using slightly modified processes readily available to those skilled in the art. It can be prepared from readily available starting materials. Although particular embodiments of the invention may be shown or described herein, those skilled in the art will appreciate that all embodiments or aspects of the invention can be implemented using the methods described herein, or It will be appreciated that it may be obtained using other known methods, reagents and starting materials. Where typical or preferred process conditions (ie, reaction temperature, time, molar ratios of reactants, solvent, pressure, etc.) are given, other process conditions can also be used, unless otherwise indicated. Optimal reaction conditions may vary depending on the particular reactants or solvents used, but such conditions can be readily determined by one of ordinary skill in the art through routine optimization procedures.

Therefore, the processes described below and reported in the schemes below should not be considered as limiting the scope of synthetic methods available for the preparation of compounds of the invention.

Compounds of formula (I), including all or at least one of the compounds listed herein, can be prepared using generally known methods according to the procedures outlined in detail in the schemes shown below.

In a first embodiment of the invention, compounds of formula (I), wherein R ₁ , L, L ₁ , Hy and X are as defined above, are as described in Scheme 1 It can be prepared as follows.

Compounds of formula (I) may be prepared according to Scheme 1, described below, which provides at least one non-limiting synthetic route for the preparation of all examples.

According to Scheme 1, intermediate V can be prepared following a one-step synthesis starting from intermediate II under suitable amide coupling reaction conditions. For example, Intermediate II can be prepared with a carboxyl group for subsequent reaction with an amine, such as T3P or HATU, in a suitable organic solvent such as DCM or DMF, generally at temperatures around RT for a period ranging from several hours to overnight. An organic base such as DIPEA or TEA can be used to react with the appropriate amine III or IV in the presence of an agent that activates the acid partner. Alternatively, intermediate III can be reacted with the appropriate amine III or IV by reacting intermediate II in the presence of TCFH and 1-methylimidazole in a suitable solvent such as DMF at RT. It can be obtained by providing a transiently activated acylimidazolinium intermediate.

In another approach, intermediate IIa is combined with a suitable amine III using, for example, butyllithium as the base, in a suitable organic solvent such as THF or dioxane at a temperature ranging from room temperature to -78 °C for several hours. Intermediate V can be obtained by direct transamidation between

Intermediate V is converted to intermediate VI by deprotection of the BOC-protected amine under acidic conditions such as trifluoroacetic acid in a suitable solvent such as but not limited to DCM for several hours at room temperature. Intermediate VI can then be synthesized with Na( OAc) ₃ BH or NaCNBH ₃ and, if necessary, a suitable dehydrating agent such as Mg ₂ SO ₄ by applying reductive amination conditions. can be converted into a compound of formula (I) having

Alternatively, compounds of formula (I) can be prepared from intermediate VI using TBTU or It can be prepared through amidation conditions with a suitable carboxylic acid X in the presence of an agent that activates the carboxylic acid partner such as HATU or T3P.

In a different approach, compounds of formula (I) are prepared from intermediate VI by applying reductive amination conditions with the appropriate bromo-aldehyde VIII, as described above, to give intermediate IX.
Palladium-catalyzed cross-coupling conditions with a suitable amine, using a suitable palladium catalyst such as RuPhos Pd G3, in a suitable solvent such as dioxane, and a suitable base such as LiHMDS at a suitable temperature, e.g. 80 °C. can be obtained by applying.

Intermediate XII is synthesized from intermediate IIb by converting Boc anhydride (to which The amine is then protected using a suitable protecting agent such as (but not limited to) a suitable protecting agent such as _H2 in a suitable solvent such as ethyl acetate at room temperature with a suitable catalyst such as palladium on carbon. It can be prepared by reducing the nitro group using a suitable hydrogen source. Intermediate XII can undergo amidation using the appropriate carboxylic acid applying appropriate amidation conditions as described above, followed by Boc deprotection carried out as described above to yield intermediate XIV. and this intermediate XIV can be reacted with a suitable aldehyde VII under reductive amination conditions as described above to give a compound of formula (I).

Alternatively, intermediate XIV can undergo amidation with a suitable carboxylic acid X using the conditions described above to give compounds of formula (I).

In another embodiment, compounds of formula (I) can be prepared according to Scheme 2.

According to Scheme 2, intermediates can be prepared by applying reducing conditions using a suitable hydrogen source such as triethylsilane. a suitable organic base such as DIPEA or TEA, in the presence of a suitable protecting group such as BOC anhydride, in a suitable organic solvent such as DCM, generally at a temperature around RT for a period ranging from several hours to overnight; Amine protection of intermediate XV using a suitable activating agent such as DMAP can provide intermediate XVI.

Hydrolysis of ester XVI can be carried out under basic conditions such as lithium hydroxide in a suitable organic solvent such as MeOH, generally at temperatures near room temperature. Intermediate XVIII can be prepared from intermediate XVI under appropriate amide coupling reaction conditions. For example, intermediates An organic base such as DIPEA or TEA can be used to react with the appropriate amine III or IV in the presence of an agent that activates the acid partner.

Intermediate XVIII is prepared by deprotecting the BOC-protected amine under suitable acidic conditions such as trifluoroacetic acid in a suitable solvent such as but not limited to DCM for several hours at room temperature. It can be converted to intermediate XIX.

Compounds of formula (I) can then be obtained from intermediate XIX using the appropriate carboxylic acid X under suitable amide coupling conditions as described above. Alternatively, intermediate XIX can be reacted with a suitable reducing agent such as Na(OAc) ₃ BH or NaCNBH ₃ in the presence of an acid such as acetic acid and optionally a coordinating agent such as titanium tetrahydroisopropoxide at room temperature. can be converted to the compound of formula (I) using the appropriate aldehyde VII by applying reductive amination conditions, optionally using a suitable dehydrating agent such as Mg ₂ SO ₄ .

In another approach, intermediate XXI is obtained from intermediate Iid by reductive amination with the appropriate aldehyde VII using the conditions described above, followed by a reductive amination in a suitable solvent such as MeOH or EtOH at room temperature. , can be prepared by hydrolysis of the ester with a suitable aqueous inorganic base such as LiOH or NaOH.

Compounds of formula (I) can be prepared from intermediate XX using a suitable base such as butyllithium or LDA in a suitable organic solvent such as THF or dioxane for several hours at a temperature in the range of -78°C. can be obtained by applying transamidation conditions with amines III or IV. Alternatively, compounds of formula (I) can be prepared from intermediate XXI in a suitable organic solvent such as DCM or DMF, generally at a temperature around RT for a period ranging from several hours to overnight, followed by a reaction such as T3P or HATU. with the appropriate amine III or IV using an organic base such as DIPEA or TEA in the presence of an agent that activates the carboxylic acid partner for reaction with the amine. can be obtained under suitable amide coupling reaction conditions. In an alternative approach, compounds of formula (I) are prepared from intermediate XXI with a suitable chlorine compound, such as thionyl chloride or oxalyl chloride, in a suitable solvent such as DCM at a temperature ranging from 0° C. to room temperature. By applying acyl chloride formation conditions with a chlorinating agent and then performing amidation, such as by treating amine IV with LiHMDS, in a suitable solvent such as THF at a suitable temperature such as -78 °C. Obtainable.

In a further embodiment, compounds of formula I can be prepared according to Scheme 3.

According to Scheme 3, intermediate XXIII can be prepared free from intermediate IIe using a suitable Lewis acid such as AlCl ₃ and a suitable acyl chloride such as acetyl chloride in a suitable solvent such as DCM. It can be prepared by applying Friedel-Craft acylation conditions. Intermediate XXIV is obtained by reducing intermediate XXIII with a suitable hydrogen source, e.g. triethylsilane, in a suitable organic solvent such as THF, under acidic conditions such as trifluoroacetic acid, generally overnight at a temperature around 0°C. can be obtained. Intermediate XXIV is synthesized with Na( The appropriate aldehyde VII is prepared by applying reductive amination conditions using a suitable reducing agent such as OAc) _3BH or _NaCNBH3 and optionally _a suitable dehydrating agent such as _Mg2SO4 . It can be converted to intermediate XXV with hydrogen. Hydrolysis of ester XXV can be carried out under basic conditions, such as lithium hydroxide, in a suitable organic solvent, such as MeOH, generally at temperatures around room temperature. Starting from intermediate XXVI, compounds of formula (I) can be prepared by converting the corresponding acyl in the presence of a suitable chlorinating reagent such as POCl ₃ or thionyl chloride in a solvent such as pyridine or DCM at 5 °C or room temperature. The chloride can be obtained by direct treatment with the appropriate amine III in a suitable solvent such as DCM at room temperature.

Various aspects of the invention described in this application are illustrated by the following examples, which are not intended to limit the invention in any way.

Preparation of intermediates and examples

Chemical names of compounds were created using Structure To Name Place IUPAC Name by PerkinElmer ChemDraw Professional 19.1.1.21.

All reagents whose synthesis is not described in the experimental part are either commercially available, are known compounds, or can be formed from known compounds by methods known by those skilled in the art.

In the following procedures, some of the starting materials are indicated by "Intermediate" or "Example" numbers and step numbers. It is provided solely as an aid to the skilled chemist.

A "similar" or "analogous" procedure is one in which such procedure involves minor changes, e.g., reaction temperature, reagent/solvent amounts, reaction time, work-up conditions, chromatographic purification conditions, etc. It means there is a possibility.

Abbreviation - meaning
t _R = retention time; Boc = tert-butoxycarbonyl; (BOC) ₂ O = Boc anhydride, di-tert-butyl dicarbonate; TEA = triethylamine; HATU = (dimethylamino)-N,N-dimethyl(3H- [1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate; TBTU=O-(benzotriazol-1-yl)-N,N,N',N' -tetramethyluronium tetrafluoroborate; DMAP = 4-dimethylaminopyridine; DMF = dimethylformamide; EtOAc = ethyl acetate; ee = enantiomeric excess; RT or rt = room temperature; THF = tetrahydrofuran; SOCl ₂ = thionyl chloride; DCM = Dichloromethane;MeOH=methyl alcohol;LCMS=liquid chromatography/mass spectrometry;HPLC=high performance liquid chromatography;PrepHPLC=preparative high performance liquid chromatography;Int.=intermediate;TLC=thin layer chromatography;d-DMSO= Deuterated dimethyl sulfoxide. NMR=nuclear magnetic resonance; DIPEA=N,N-diisopropylethylamine; UPLC=ultra-performance liquid chromatography; tBu XPhos=2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl; PdCl ₂₍ dppf)=[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II);STAB=sodium triacetoxyborohydride;Pd(OAc) ₂ =palladium(II) acetate;AcOH=acetic acid;Py = pyridine; T3P = propanephosphonic anhydride; NaBH ₃ CN = sodium cyanoborohydride; Na ₂ SO ₄ = sodium sulfate; pTLC = preparative thin layer chromatography; FCC = flash column chromatography; nBuLi = n-butyl lithium; ACN=acetonitrile; _NaHCO3 =15% or saturated solution of sodium bicarbonate (sat.aq.sol.);RuPhos Pd G3:(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate, 3rd generation SCX = strong cation exchange; SFC = supercritical fluid chromatography; SM = starting material; eq .=equivalent.

Xphos Pd G2=(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II ) methanesulfonate, 2nd generation; -biphenyl)]palladium(II) methanesulfonate, 3rd generation.

General experimental details and methods
NMR characterization
¹ H NMR spectrum, VarianMR-400 spectrometer operating at 400MHZ (proton frequency) with self-shielded Z gradient coil 5mm 1H/nX broadband probe head for reverse detection, deuterium digital locking channel unit, orthogonal digital with transmitter offset frequency shift Alternatively, ¹ H NMR spectra were recorded on a Bruker Avance III HD 400MHz or Bruker Fourier 300MHz. Chemical shifts are reported in 6 ppm relative to trimethylsilane (TMS) as internal standard. Coupling constants (J values) are given in hertz (Hz), and multiplicity is reported using the following abbreviations (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br. s = broad singlet, nd = undetermined).

NH signals of amide bonds or amine bonds (exchangeable protons) may not be visible. The CH ₂ signal of the indoline ring may be hidden under the water or DMSO signal. The CH ₂ signal of the pyrrolidine ring or 1-methylpiperazine ring may be hidden by the water or DMSO signal. The CH ₃ signal may be hidden by the water or DMSO signal.

LC/UV/MS analysis method
LC/MS retention times are estimated to be subject to experimental error of ±0.5 min.

Method 1: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 2: Acquity UPLC HSS C18 column, 100x2.1mm, 1.8μm (Plus Guard Cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid) from 5% to 95% within 5.6 minutes. Flow rate: 0.4ml/min. Wavelength: 210-400nm DAD. UPLC + Waters DAD + Waters SQD2, single quadrupole UPLC-MS

Method 3: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 95% to 20% within 4.75 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 4: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 90% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 5: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 70% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 6: Acquity CSH C18 column 50mmx2.1mm 1.7μm, maintained at 40°C; Mobile phase: Eluent B (MeCN/Water 95:5 +0.05 in Eluent A (Water/MeCN 95:5 +0.05%HCOOH) %HCOOH) from 1% to 99.9% within 1.5 minutes. Flow rate: 1mL/min Wavelength: 210-400nm DAD. UPLC + Waters PDA + Waters QDA.

Method 7: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 8: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (without formic acid) in MeCN (without formic acid), 60% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 9: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 60% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific ISQ EC Mass Spectrometer with DAD Detector.

Method 10: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 70% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific ISQ EC Mass Spectrometer with DAD Detector.

Method 11: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 12: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 75% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector

Method 13: ACQUITY UPLC BEH C8 column, 42.1x150mm, 1.7μm, maintained at 55°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 10% within 7.00 min; flow rate: 0.5 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 14: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 50% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-350 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific ISQ EC with DAD Detector - Mass Spectrometer

Method 15: Gemini-NX C18 column, 4.6x150mm, 3μm, maintained at 35°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 8.50 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific MSQ Plus with DAD detector.

Method 16: Kinetex® XB-C18 column, 4.6x50mm, 2.6μm, maintained at 25°C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), 60% to 5% within 3.90 min; flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000/Thermo Scientific ISQ EC mass spectrometer with DAD detector.

Method 20: Acquity UPLC BEH C18, 100x2.1mm, 1.7μm, maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), from 5% to 80% within 1.5 min; flow rate: 1.5 ml/min; wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and Qda.

Method 21: Acquity BEH UPLC column, 2.1x50mm, 1.7μm, maintained at 40°C. Mobile phase: MeCN (0.03% ammonia) in water (0.03% ammonia), from 8% to 97% within 1.5 min; flow rate: 0.8 ml/min; wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and QDa.

Method 22: Waters Sunfire C18 column, 4.6x50mm, 3.5μm, maintained at 40°C. Mobile phase was MeCN+10mM ammonium bicarbonate in water, from 5 to 95% within 2.5 minutes. Flow rate: 2.0ml/min. Wavelength: 210-400nm DAD. Waters 2795 Separation Module + Waters DAD + Micromass ZQ, Single Quadrupole LC-MS

Chiral Supercritical Fluid Chromatography (SFC) Separation Protocol Diastereomeric separation of compounds was performed using a Waters Thar Prep100 preparative SFC system (P200 CO ₂ pump, 2545 modifier pump, 2998 UV/VIS detector, 2767 stacked injection module) This was achieved by supercritical fluid chromatography (SFC) using a liquid handler). A Waters 2767 liquid handler served as an autosampler and fraction collector. Suitable isocratic methods were selected based on methanol, ethanol or isopropanol solvent systems under unmodified or basic conditions. The standard SFC method used modifier, CO ₂ , 100 mL/min, back pressure 120 Bar, column temperature 40°C. The modifier used under basic conditions was diethylamine (0.1% V/V). Modifiers used under acidic conditions were formic acid (0.1% V/V) or trifluoroacetic acid (0.1% V/V). SFC purification was monitored by Waters Fractionlynx software from 210 to 400 nm and controlled by triggering at a threshold collection value (typically 260 nm). The collected fractions were analyzed by SFC (Waters/Thar SFC system and Waters SQD). Fractions containing the desired product were concentrated by vacuum centrifugation.

Supercritical fluid chromatography-mass spectrometry analysis conditions:

Method 17: SFC-MS used a YMC AMYLOSE-C column (45% IPA/CO ₂ (containing 0.1% diethylamine) isocratic run, 100 mL/min, back pressure 120 Bar, column temperature 40 °C). This was done with a Waters/Thar SFC system with Waters SQD.

Method 18: SFC-MS was performed using a Lux C1 (21.2 mm × 250 mm, 5 um) column (isocratic run (50:50 hexane:EtOH, 0.2% v/v NH3), 21 mL/min, column temperature 30 °C). A Gilson preparative LC system (Gilson Pump - 333; Gilson 151; Gilson Valvemate 6 position) was used.

Method 19: SFC-MS was performed using a Lux C1 (4.6 mm × 250 mm, 5 um) column (isocratic run (50:50 HEX:EtOH (0.2% v/v NH3), 1 mL/min, column temperature 30 °C). A Gilson preparative LC system was used.

If the preparation of starting materials is not described, these are commercially available, known in the literature, or readily available to those skilled in the art using standard procedures. All solvents were commercially available and used without purification.

Using reversed-phase (C18) preparative HPLC, both basic conditions (ACN+0.1%NH ₃ , H2O+0.1%NH ₃ ) and acidic conditions ((ACN+0.1%FA, H ₂ O+0.1%FA) Preparative HPLC was performed on both and in the last case, unless otherwise stated, the residue was triturated with _NaHCO (15% aq. sol.) and the precipitate was filtered through a shot funnel, rinsed with water and placed in a vial. The free base of the product was obtained by transferring and drying under high vacuum overnight at room temperature or using SCX(NH).

Thin layer chromatography was performed on Merck silica gel 60 F254 TLC plates. Preparative thin layer chromatography (pTLC) was performed on Uniplate 1000 micron or 500 micron silica gel plates.

Flash chromatography (FCC) was performed using Interchim PuriFlash 450 and 520Plus systems or Isolera ^™ flash purification systems using pre-packed silica gel cartridges unless otherwise noted in the text.

Preparation of Intermediates Lithio 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate - Preparation of Intermediate 1

Step 1: Methyl 3-bromo-5-(trifluoromethyl)benzoate-Intermediate 2

To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (75.0 g, 279 mmol) in MeOH (282 mL) at 0 °C was added SOCl ₂ (81.0 mL, 1115 mmol) dropwise. The reaction mixture was then stirred under reflux overnight, after which the volatiles were removed under vacuum. Water (200 mL) was added to the residue and the aqueous phase was extracted with EtOAc (2x250 mL). The organic phases were combined, washed with a saturated solution of NaHCO ₃ , dried over Na ₂ SO ₄ and concentrated under vacuum to give the title compound (74.5 g, 94%).

^1H NMR (300 MHz, DMSO-d6) δ 8.30 (dt, J = 1.8, 0.8 Hz, 2H), 8.13 (td, J = 1.6, 0.8 Hz, 1H), 3.90 (s, 3H).

Step 2: Methyl 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate - Intermediate 3

Intermediate 2 (47.5 g, 168 mmol), Cs ₂ CO ₃ (164 g, 503 mmol), potassium 1-methyl-4-tritrifluoroborate methylpiperazine (40.6 g, 184.6 mmol), THF (100 mL) and water (11 mL) suspended in a mixture of The suspension was degassed, then Pd(OAc) ₂ (3.76 g, 16.8 mmol) and XPhos (16.0 g, 33.5 mmol) were added and the reaction was carried out at 80° C. for 24 h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (2x150 mL). The organic phases were combined, concentrated and dried under vacuum to give the crude product, which was purified by column chromatography eluting with DCM/MeOH (9:1) to give the title compound (25.3 g, 48%).

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.16 (d, J = 1.7 Hz, 1H), 8.07 (t, J = 1.8 Hz, 1H), 7.97 - 7.86 (m, 1H), 3.90 (s, 3H), 3.62 (s, 2H), 2.38 (s, 8H), 2.15 (s, 3H).

Step 3: Lithio 3-[(4-methylpiperazin-1-yl)methyl]-5-(trifluoromethyl)benzoate-Intermediate 1
Intermediate 3 (25.3 g, 80.0 mmol) was dissolved in MeOH (700 mL). 1M LiOH solution (3.8g, 160mL) was added to the reaction mixture and stirred overnight at RT. The solvent was removed under vacuum and the crude material was triturated with diethyl ether (2x) and filtered. The solid was collected to give the title compound (26.0g, 100%).

^1H NMR (300 MHz, DMSO-d6) δ 8.02 (s, 2H), 7.49 (s, 1H), 3.51 (s, 2H), 2.32 (s, 8H), 2.14 (s, 3H).

Preparation of 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde-intermediate 4

Step 1: 2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidine-5-carbaldehyde-intermediate 4

2-chloropyrimidine-5-carbaldehyde (50 mg, 0.351 mmol) was dissolved in THF (3.5), then 1-methyl-1H-pyrazol-4-amine (41 mg, 0.421 mmol), TEA (0.1 ml, 0.719 mmol) and THF (3.5 ml) were added. The reaction mixture was stirred at room temperature overnight. The mixture was quenched by adding DCM and brine. Phase separation was performed and the aqueous phase was washed with DCM (x2). All organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by FCC eluting with hexane/ethyl acetate (1:1) to give the title compound (35 mg, 39%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.80 (s, 1H), 8.92 - 8.79 (m, 2H), 7.99 (d, J = 0.8 Hz, 1H), 7.56 (d , J = 0.8 Hz, 1H), 3.83 (s, 3H).

Preparation of 3-(morpholinomethyl)-5-(trifluoromethyl)aniline-intermediate 5

Step 1: 4-(3-nitro-5-(trifluoromethyl)benzyl)morpholine-Intermediate 6

3-Nitro-5-(trifluoromethyl)benzaldehyde (150 mg, 0.685 mmol) and morpholine (0.066 mL, 0.753 mmol) were dissolved in DCM (6.8 ml) and titanium(IV) isopropoxide (389.4 mg, 1.37 mmol) ) and acetic acid were added. The reaction mixture was stirred at room temperature for 1 h. STAB (290 mg, 1.37 mmol) was added and the reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material. The reaction mixture was partitioned between DCM and saturated NaHCO _{3 (aq)} and the mixture was filtered through a bed of Celite. The aqueous phase was extracted with 2xDCM and the organic phases were combined, washed with saturated aqueous NaCl _(aq) , separated and concentrated under vacuum to give the title compound (197mg, 99%).

¹ H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 3.76 - 3.73 (m, 4H), 3.66 (s, 2H), 2.51 - 2.48 (m, 4H)

The following compounds were prepared by reacting the appropriate corresponding amines as described for Step 1 of Intermediate 6.

Step 2: 3-(morpholinomethyl)-5-(trifluoromethyl)aniline-intermediate 5
To palladium (10% on carbon) (10 wt%) was added a solution of intermediate 6 (153 mg, 0.527 mmol) in ethanol (5 ml). The flask was evacuated and purged with argon (x3), then evacuated and purged with hydrogen (x3). The reaction mixture was stirred at room temperature until LCMS showed consumption of starting material. The reaction mixture was diluted with DCM and filtered through Celite. The filter cake was washed with DCM and the filtrates were combined and concentrated under vacuum to give the title compound (134 mg, 98%).

¹ H NMR (400 MHz, CDCl3) δ 6.95 (s, 1H), 6.84 (s, 2H), 6.79 (s, 1H), 3.82 (s, 2H), 3.74 - 3.69 (m, 4H), 3.44 - 3.43 (m, 2H), 2.46 - 2.43 (m, 4H).

The following compounds were prepared as described for step 2 of intermediate 5 starting from the appropriate corresponding intermediates 7 and 8 described above in step 1.

Preparation of 3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)aniline-intermediate 11

Step 1: 3-(trifluoromethyl)-5-vinyl-aniline-intermediate 12

3-amino-5-bromobenzotrifluoride (2.50g, 10.4mmol, 1.00eq), vinylboronic acid pinacol ester (2.10mL, 12.5mmol, 1.20eq), XPhos Pd G3 (441mg, 0.521mmol, 0.05eq), XPhos (497 mg, 1.04 mmol, 0.1 eq) and K ₃ PO ₄ (5527 mg, 26.0 mmol, 2.5 eq) was suspended in 1,4-dioxane (45 mL) and water (5 mL). The reaction mixture was sparged with argon for 15 min and stirred at 80°C for 1.5 h. The reaction mixture was allowed to cool to room temperature and was partitioned between water and EtOAc. The aqueous phase was extracted with 2xEtOAc and the organic phases were combined, washed with saturated NaCl(aq), dried ( _MgSO4 ) and concentrated. The residue was purified by FCC eluting with 0-30% EtOAc in cyclohexane to give the title compound (1.54g, 79%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.04 (s, 1H), 6.85 (s, 1H), 6.79 (s, 1H), 6.64 (dd, J=11.0, 17.5 Hz, 1H), 5.75 (d, J=17.5 Hz, 1H), 5.30 (d, J=11.0 Hz, 1H), 3.86 (br s, 2H)

The following intermediate C was prepared by reacting the appropriate corresponding bromide as described for intermediate 12 in step 1. Such procedures may include minor modifications. In some cases, if changes involved chromatographic purification conditions (eg, prepHPLC or flash chromatography) or catalysts (eg, XPhos Pd G3 or XPhos Pd G2), such changes were reported in the table.

Step 2: tert-butyl N-[3-(trifluoromethyl)-5-vinyl-phenyl]carbamate - intermediate 13

To a mixture of Intermediate 12 (500 mg, 2.67 mmol, 1.00 eq) and di-tert-butyl dicarbonate (0.77 mL, 3.34 mmol, 1.25 eq) was added toluene (5 mL). The reaction mixture was stirred at 100° C. for 19 h, allowed to cool to RT and concentrated under vacuum. The residue was diluted with heptane and partially concentrated resulting in the formation of a thick precipitate. The suspension was filtered under vacuum to give the title compound (488mg, 64%). The filtrate was concentrated in vacuo and the residue was purified by FCC eluting with EtOAc in cyclohexane (0-10%) to give the title compound (150 mg, 20%). Combined yield = 638 mg, 84%.

¹ H NMR (400 MHz, CDCl ₃ ) δ 7.59 - 7.54 (m, 2H), 7.32 (s, 1H), 6.69 (dd, J=11.0, 17.5 Hz, 1H), 6.56 (s, 1H), 5.81 ( d, J=17.5 Hz, 1H), 5.35 (d, J=11.0 Hz, 1H), 1.53 (s, 9H)

The following intermediate 47 was prepared as described for intermediate 13 in step 2.

Step 3: tert-butyl N-[3-formyl-5-(trifluoromethyl)phenyl]carbamate - intermediate 14

At −78° C., ozone was passed through a solution of intermediate 13 (488 mg, 1.70 mmol, 1.00 eq) in DCM (20 mL) for 30 min, at which point a light blue color was observed. Dimethyl sulfide (0.62 mL, 8.49 mmol, 5.00 eq) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was concentrated under vacuum and the residue was purified by column silica gel chromatography (ethyl acetate/cyclohexane, 0-20%) to give the title compound (278 mg, 57%).

¹ H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 8.06 (s, 1H), 7.98 (s, 1H), 7.80 (s, 1H), 6.76 (s, 1H), 1.54 (s, 9H) ).

The following intermediate 48 was prepared as described for intermediate 14 in step 3.

Step 4: tert-butyl N-[3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl) phenyl]carbamate - intermediate 15

A solution of intermediate 14 (140 mg, 0.484 mmol, 1.00 eq) in DCM (3.5 mL) was added with pyrrolidine (440 μL, 0.532 mmol, 1.10 eq), acetic acid (83 μL, 1.45 mmol, 3.00 eq) and titanium(IV) Propoxide (290 μL, 0.968 mmol, 2.00 eq) was added. The reaction mixture was stirred at room temperature for 1 h. STAB (205 mg, 0.968 mmol, 2.00 eq) was added and the reaction mixture was stirred for an additional 1.5 h at room temperature. The reaction mixture was partitioned between saturated NaHCO _{3 (aq)} and EtOAc. The aqueous phase was re-extracted with 3xEtOAc and the organic phases were combined, washed with water, saturated NaCl _(aq) , separated and concentrated under vacuum to give the title compound.

¹ H NMR (400 MHz, CDCl3) δ 7.65 (s, 1H), 7.44 (s, 1H), 7.27 (s, 1H), 6.58 (s, 1H), 3.63 (s, 2H), 2.55 - 2.50 (m , 4H), 1.81 - 1.77 (m, 4H), 1.52 (s, 9H).

The following intermediate 49 was prepared as described for intermediate 15 in step 4. Intermediate 49 was used in the next step without further purification.

Step 5: 3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)aniline-intermediate 11
To a solution of intermediate 15 (186 mg, 0.540 mmol, 1.0 eq) in MeOH (3.0 ml) was added 4M HCl in dioxane (0.41 ml, 1.62 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 2 h. Further 4M HCl in dioxane (0.41 mL, 1.62 mmol, 3.00 eq) was added and the reaction mixture was stirred at room temperature for an additional 4 h. 4M HCl in dioxane (0.41 mL, 1.62 mmol, 3.00 eq) was added and the reaction mixture was stirred for an additional 12 h. The reaction mixture was concentrated under vacuum to give the HCl salt of the title compound (140 mg, 90%).

¹ H NMR (400 MHz, DMSO) δ 10.64 (s, 1H), 7.12 (s, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 4.27 (d, J=6.0 Hz, 2H), 3.37 - 3.31 (m, 2H), 3.07 - 2.98 (m, 2H), 2.03 - 1.96 (m, 2H), 1.91 - 1.86 (m, 2H)

The following intermediate 50 was prepared as described for intermediate 11 in step 5.

Preparation of 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline-intermediate 16

Step 1: 3-(4-nitro-2-(trifluoromethyl)phenoxy)tetrahydrofuran-intermediate 17

Sodium hydride (60% in mineral oil, 158 mg, 6.60 mmol) was added to a stirred solution of 3-hydroxytetrahydrofuran (0.53 g, 6.00 mmol) in acetonitrile (13 ml) under an inert atmosphere. The reaction mixture was stirred for 1 h, then 2-fluoro-5-nitrobenzotrifluoride (0.69 mL, 5.00 mmol) was added in one portion. The reaction mixture was stirred at room temperature until LCMS showed consumption of starting material. The reaction mixture was partitioned between water and DCM and the aqueous phase was re-extracted with DCM (x2). The organic phases were combined, separated and concentrated under vacuum to give the title compound (1.52g, 99%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.52 (d, J=3.0 Hz, 1H), 8.42 (dd, J=3.0, 9.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 1H), 5.16 - 5.12 (m, 1H), 4.15 - 4.11 (m, 1H), 4.03 - 3.97 (m, 3H), 2.35 - 2.19 (m, 2H)

The following compounds were prepared as described for step 1 in intermediate 17 starting from the appropriate corresponding alcohol.

Step 2: 4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)aniline-Intermediate 16

The required intermediate 17 (1.52g, 5.48mmol) and iron powder (1.53g, 27.4mmol) were combined in acetic acid (18ml) and methyl alcohol (18ml). The reaction mixture was stirred at 50° C. until LCMS showed consumption of starting material. The stirred mixture was allowed to cool to room temperature and concentrated under vacuum. The residue was partitioned between DCM and saturated Na ₂ CO ₃ (aq). The organic phases were combined, separated and concentrated under vacuum. The residue was loaded onto an Isolute SCX cartridge, washed with DCM/MeOH, then eluted with 2M _NH3 /MeOH. The eluate was concentrated to give the title compound (1.10 g, 75%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 6.91 (d, J=2.0 Hz, 1H), 6.79-6.79 (m, 2H), 4.92 - 4.87 (m, 1H), 4.04 - 3.90 (m, 4H), 3.56 (s, 2H), 2.18 - 2.10 (m, 2H)

The following compounds were prepared via reduction of the nitro residue as described for intermediate 16, starting from the appropriate corresponding nitro derivatives.

Preparation of 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline-intermediate 20

Step 1: 4-(2-(3-nitro-5-(trifluoromethyl)phenoxy)ethyl)morpholine-Intermediate 21

To a solution of 3-nitro-5-(trifluoromethyl)phenol (480.5 mg, 2.32 mmol) in N,N-dimethylformamide (12 ml) was added 4-(2-chloroethyl)morpholine hydrochloride (431 mg, 2.32 mmol). (1.20eq) was added followed by cesium carbonate (1.5g, 4.64mmol). The mixture was stirred at 80° C. until LCMS showed consumption of starting material. The reaction mixture was diluted with water and extracted with DCM (x2). The organic phases were combined and concentrated.

The residue was purified by FCC eluting with EtOAc in cyclohexane (0-100%) to give the title compound (0.6g, 97%).

¹ H NMR (400 MHz, DMSO) δ 8.05 (d, J=2.5 Hz, 2H), 7.81 (s, 1H), 4.34 (dd, J=5.6, 5.6 Hz, 2H), 3.58 (dd, J=4.6 , 4.6 Hz, 4H), 2.74 (dd, J=5.6, 5.6 Hz, 2H), 2.52 (s, 4H), 2.51 (ddd, J=5.5, 5.5, 4.3 Hz, 4H).

The following intermediate 51 was prepared as described for intermediate 21 in step 1.

Step 2: 3-(2-morpholinoethoxy)-5-(trifluoromethyl)aniline-intermediate 20

Intermediate 21 (100 mg, 0.312 mmol) in ethanol (3 ml) was added with 1-methyl-1,4-cyclohexadiene (881 mg, 9.36 mmol) and palladium on carbon (10%) (33 mg, 0.312 mmol) were added sequentially and the reaction mixture was stirred at 80° C. until LCMS indicated consumption of starting material. The reaction mixture was allowed to cool to room temperature and filtered through a pad of Celite, which was washed with ethanol and ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (84 mg, 93%).

¹ H NMR (400 MHz, CDCl3) δ 6.52 (d, J=9.5 Hz, 2H), 6.36 (t, J=2.0 Hz, 1H), 4.09 (t, J=5.6 Hz, 2H), 3.83 (s, 2H), 3.75 - 3.72 (m, 4H), 2.79 (t, J=5.7 Hz, 2H), 2.59 - 2.55 (m, 4H).

The following intermediate 52 was prepared as described for intermediate 20 in step 2.

Preparation of 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

Intermediate 53
Step 1: 3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde

1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (100 mg, 0.684 mmol, 1.00 eq) and N,N-dimethylmethyleneiminium iodide (190 mg, 1.03 mmol, 1.50 eq) were dissolved in acetonitrile (5.00 mg, 1.03 mmol, 1.50 eq). mL) and heated at 80° C. with stirring overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (20.00 mL), pH was adjusted to 12 with 1N NaOH, and extracted with DCM. The organic phases were combined, filtered through a hydrophobic frit, and the solvent was concentrated under reduced pressure. The resulting material was washed with 1:1 cyclohexane/diethyl ether and filtered to give the title compound (64 mg, 46%).

¹ H NMR (400 MHz, CDCl3) d 10.14 (s, 1H), 10.05 - 10.05 (m, 1H), 8.84 (s, 1H), 8.59 (s, 1H), 7.39 (s, 1H), 3.66 (s , 2H), 2.30 (s, 6H)

Preparation of 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde intermediate 54

Step 1: 3-bromo-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde

To a solution of 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (650 mg, 4.42 mmol, 1.00 eq) in N,N-dimethylformamide (20 mL) at 20 °C was added N-bromosuccinimide (983 mg). , 5.52 mmol, 1.25 eq) was added. The reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with sat.aq.NH ₄ Cl (100 mL) and extracted with EtOAc. The organic phases were combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The material was triturated with water and dried under reduced pressure to give the title compound (1.02g, 99.2% yield).

¹ H NMR (400 MHz, DMSO) δ 14.61 - 14.58 (m, 1H), 10.23 (s, 1H), 9.13 (d, J=1.8 Hz, 1H), 8.73 (d, J=1.5 Hz, 1H)

Preparation of 2-((4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-amine

intermediate 55

Step 1: 4-amino-N-methoxy-N-methyl-6-(trifluoromethyl)picolinamide intermediate 56

A mixture of 4-amino-6-(trifluoromethyl)picolinic acid (445 mg, 2.16 mmol) and HATU (1.6 g 4.32 mmol) in DMF (0.1 M concentration) was added with N,N-diisopropylethylamine (2.9 mL, 17.98 mmol) was added. The reaction mixture was stirred at room temperature for 15 minutes, then N,O-dimethylhydroxylamine hydrochloride (232 mg, 2.37 mmol) was added. The reaction mixture was stirred until LCMS showed consumption of starting material, then concentrated. Purification by column silica gel chromatography (80 g cartridge, 0-50% EtOAc (+0.1% NEt ₃ ) in cyclohexane) gave the title compound (369 mg, 68%).

¹ H NMR (400 MHz, DMSO) δ 6.96 (d, J=2.1 Hz, 1H), 6.84 - 6.78 (m, 3H), 3.67 (s, 3H), 3.24 (s, 3H)

Step 2: 4-amino-6-(trifluoromethyl)picolinaldehyde

intermediate 57

To a stirred solution of intermediate 56 (308 mg, 1.24 mmol) in THF (4.82 mL) cooled in an ice/water bath was added LiAlH ₄ (2M in THF, 0.62 mL, 1.24 mmol) while maintaining an internal temperature of 6 °C. was dripped. The reaction mixture was stirred for 1 h and diluted with anhydrous diethyl ether (5 mL). Water (47 μL), 15% NaOH _(aq) (47 μL) and water (141 μL) were added and the reaction mixture was warmed to room temperature and stirred for 15 minutes. Anhydrous _MgSO4 was added, the reaction mixture was stirred for 15 min, filtered, and the filtrate was concentrated under reduced pressure to yield intermediate 57 (252 mg, >100%), which was carried on to the next step without purification. It was used in

LCMS (Method 21) _tR : 0.95 min, m/z (M+1); 191

Step 3: 2-((4-methylpiperazin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-amine

intermediate 55
A solution of intermediate 57 (126 mg, 0.663 mmol) in DCM (0.1 M concentration) was added with methylpiperazine (0.074 mL, 0.663 mmol) titanium(IV) isopropoxide (376.87 mg 1.326 mmol, 2.00 eq) and acetic acid (114 μL). , 1.988 mmol eq) was added. The reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (281 mg, 1.325 mmol) was added and the reaction mixture was stirred at room temperature until LCMS indicated consumption of starting material. Purification by column silica gel chromatography (0-10% 2M NH ₃ /MeOH in DCM) gave the title compound (85 mg, 46%).

The following intermediates were prepared as described for intermediate 55 in step 3 starting from intermediate 57 using the appropriate commercially available amine.

Preparation of 3-amino-N-[2-(dimethylamino)ethyl]-5-(trifluoromethyl)benzamide

intermediate 60

Step 1: 3-amino-N-[2-(dimethylamino)ethyl]-5-(trifluoromethyl)benzamide intermediate 60

To a mixture of the required carboxylic acid (0.25 g, 1.21 mmol) and HATU (0.9, 2.43 mmol) in DMF (0.1 M concentration) was added N,N-diisopropylethylamine (639 μL, 3.66). The reaction mixture was stirred at rt for 15 min, then N,N-dimethylethylenediamine (0.13g mg, 1.46mmol) was added. The reaction mixture was stirred at room temperature until LCMS showed consumption of starting material, then concentrated. The residue was purified by column silica gel chromatography (12g cartridge, 0-10% 2M _NH3 /MeOH in DCM) to give the title compound (237mg, 71%).

¹ H NMR (300 MHz, DMSO) δ 8.51 (t, J=5.5 Hz, 1H), 7.28 - 7.25 (m, 1H), 7.25 - 7.21 (m, 1H), 6.99 - 6.96 (m, 1H), 5.78 (s, 2H), 3.44 (q, J=6.3 Hz, assumed 2H, overlapping with water peak), 2.75 (t, J=6.2 Hz, 2H), 2.46 (s, 6H)

The following intermediates were prepared as described for intermediate 60, varying the corresponding commercially available amines.

Preparation of Examples

Example 1: Compound 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl ) Preparation of indoline-6-carboxamide

Step 1: tert-butyl 6-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate-Intermediate 22

1-(tert-butoxycarbonyl)indoline-6-carboxylic acid (1 g, 3.80 mmol) and 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (0.916 g, 3.80 mmol) was dissolved in DCM (2 ml). DIPEA (1.990ml, 11.39mmol) and 50% T3P (4.48ml, 7.60mmol) in ethyl acetate were added. The reaction mixture was stirred at 20°C for 20hr. The reaction mixture was diluted with DCM (10ml) then water (5ml) was added. Phase separation was performed and the organic phase was washed with citric acid (5% aq.sol., _2x10ml ), dried over _Na2SO4 , filtered and concentrated to dryness. The crude material was purified via column chromatography eluting with DCM/MeOH, 100% DCM to 5% MeOH in DCM. 200 mg of pure desired product was obtained. A mixture of 1.4 g of desired product and starting material (acid) was obtained. This material was dissolved in DCM (100ml) and washed with Na ₂ CO ₃ (3x50ml) and brine (100ml) to remove residual acid. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give the title compound (1.01 g, 55%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.20 (d, J = 1.4 Hz, 1H), 8.14 (s, 1H), 7.71 (d, J = 2.1 Hz, 1H), 7.58 (dd, J = 7.7, 1.7 Hz, 1H), 7.49 (t, J = 1.3 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 3.98 (t, J = 8.7 Hz, 2H), 3.15 (t, J = 8.7 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.53 (s, 8H).

Step 2: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide-intermediate 23

Intermediate 22 (1.01g, 2.076mmol) was dissolved in DCM (5ml) and then trifluoroacetic acid (1.440ml, 18.68mmol) was added. The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM (10ml) and NaHCO ₃ (sat.aq.sol.) was added. The mixture was stirred at room temperature for 30 minutes (foaming was observed). The phase was distributed. The organic phase was washed with _NaHCO3 , dried _{over Na2SO4} and evaporated under vacuum. The material was used without further purification. The title compound was obtained as free base (900 mg, 100%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.49 (s, 1H), 8.31 (dd, J = 4.2, 2.1 Hz, 2H), 8.17 (d, J = 1.7 Hz, 1H), 7.71 (d, J = 1.8 Hz, 1H), 7.53 (d, J = 1.4 Hz, 1H), 7.25 - 7.13 (m, 2H), 7.06 (d, J = 1.3 Hz, 1H), 3.47 (d, J = 8.5 Hz, 3H) ), 2.98 (t, J = 8.5 Hz, 2H), 2.20 (d, J = 1.0 Hz, 3H).

Step 3: 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline -6-carboxamide (Example 1)

N-(3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide (0.1 g, 0.259 mmol) was dissolved in DCM (2 ml) and then To this were added imidazo[1,2-a]pyridine-3-carbaldehyde (0.038g, 0.259mmol), _NaCNBH3 (0.024g, 0.388mmol) and AcOH (0.030ml, 0.518mmol). The reaction mixture was stirred at 20°C for 18 hours. The reaction mixture was evaporated, then diluted with DCM (5ml), then water (5ml) was added. The phases were partitioned and the organic phase was washed with 2x10 ml of _K2CO3 ( _aq.sat.sol .), dried over _Na2SO4 , filtered and concentrated under reduced pressure _. The crude material was purified via preparative HPLC eluting with ACN+0.1% _NH3 , H2O+0.1% _NH3 to give the title compound (28mg, 21%).

The following compounds were prepared by reductive amination as described for steps 1-3 of Example 1, starting from the appropriate corresponding commercially available carbaldehyde in step 3; NaCNBH as reducing agent. If STAB is used instead of ₃ , it is shown in the table along with the equivalent weight (eq.).

Example 9: 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(tri Preparation of fluoromethyl)phenyl)indoline-6-carboxamide

Step 1: tert-butyl 6-((3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate-intermediate 24

Dry (heat gun/vacuum/N2 cycle) 3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)aniline (0.542 g, 1.983 mmol) anhydrous in a two-necked 25 mL flask. Dissolved in THF (15ml) and cooled to -78°C, then butyllithium (0.793ml, 1.983mmol) was added dropwise. The solution was stirred for 15 minutes, then a solution of 1-(tert-butyl) 6-methylindoline-1,6-dicarboxylate (0.275 g, 0.992 mmol) in anhydrous THF (1 mL) was added dropwise. The mixture was stirred for 16 hours while warming from -78°C to room temperature. Water (50 mL) was added followed by extraction with EtOAc (3x10 mL). The organic phase was washed with brine (30 mL), dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude material was purified on FCC (Biotage® Sfar KP-Amino D -Duo) system eluting with DCM/MeOH (100:0 to 90:10) to give the title compound (518 mg, 100% ) was obtained.

^1H NMR (DMSO-d6, 400MHz): δ = 10.48 (s, 1H), 8.15 (s, 1H), 7.99 (s, 1H), 7.57 (d, 1H, J = 7.7 Hz), 7.36-7.32 ( m, 2H), 6.76 (s, 1H), 5.51 (s, 2H), 3.97 (t, 2H, J = 8.7 Hz), 3.14 (t, 2H, J = 8.7 Hz), 2.33 (bs, 8H), 2.15 (s, 3H), 1.53 (s, 9H) ppm

The following intermediate 62 was prepared following the same procedure used for the synthesis of intermediate 24, varying the corresponding commercially available amine.

Step 2: N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide-intermediate 25

Intermediate 24 (0.514g, 0.991mmol) was dissolved in a 3:1 mixture of DCM (12ml) and 2,2,2-trifluoroacetic acid (3.04ml, 39.6mmol). The solution was stirred at room temperature for 1 h. The solvent was evaporated. The crude was diluted with water (20 mL) and then the pH was adjusted to about 7-8. The product was extracted with DCM (2x20mL) via a phase separator. The organic phase was concentrated to dryness to give the title compound (415 mg, 100%).

^1H NMR (DMSO-d ₆ , 400MHz): δ = 10.25 (s, 1H), 8.13 (s, 1H), 7.96 (s, 1H), 7.28 (s, 1H), 7.15 (d, 1H, J = 7.5 Hz), 7.11 (d, 1H, J = 7.5 Hz), 7.01 (s, 1H), 4.04 (q, 1H, J = 5.1 Hz), 3.49 (s, 2H), 3.44 (t, 2H, J = 8.7 Hz), 2.94 (t, 2H, J = 8.7 Hz), 2.34-2.27 (m, 8H), 2.13 (s, 3H) ppm The following intermediate 63 was prepared following the same procedure reported for intermediate 25. Prepared. Changes in chromatographic purification conditions are reported in the table.

Step 3: 1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoro Methyl)phenyl)indoline-6-carboxamide (Example 9)

Intermediate 25 (0.1 g, 0.239 mmol) was dissolved in DCM (2 ml), then 1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (0.035 g, 0.239 mmol), _NaCNBH (0.023 g, 0.358 mmol) and AcOH (0.027 ml, 0.478 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (5ml) and washed with water (5ml). The organic phase was washed with _K2CO3 (aq.sat.sol., _2x10ml ), dried over _Na2SO4 , filtered and concentrated under reduced pressure _.

The crude material was purified via preparative HPLC eluting with ACN+0.1% FA, _H2O +0.1% FA. The residue was triturated with NaHCO ₃ (15% aq.sol.) and the precipitate was filtered through a shot funnel, rinsed with water, transferred to a vial and dried overnight at room temperature under high vacuum to give the title compound ( 17 mg, 13%).

The following compounds were prepared starting from the appropriate corresponding commercially available or synthetic carbaldehyde in step 3 and using NaCNBH ₃ or STAB as the reducing agent as described for steps 1-3 of Example 9. , prepared via reductive amination. In some cases, titanium (IV) isopropoxide was used as the reducing agent. These changes were reported in the table.

Example 12: 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) Preparation of indoline-6-carboxamide

Step 1: N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(2-(methylcarbamoyl)isonicotinoyl)indoline-6-carboxamide ( Example 12)

Imidazo[1,2-a]pyridine-3-carboxylic acid (0.040g, 0.246mmol) was dissolved in DMF (2.5ml), then TBTU (0.079g, 0.246mmol), TEA (0.069ml, 0.492mmol) ) was added. The mixture was stirred at room temperature for about 15 minutes, then Intermediate 23 (0.095g, 0.246mmol) was added. The reaction mixture was stirred at room temperature overnight.

The reaction mixture was diluted with DCM (5ml) and water (5ml). The mixture was stirred at room temperature for 15 min, then the phases were separated and the organic phase was washed with water (2x15ml) and brine ( _2x5ml ), then dried over _Na2SO4 , filtered and reduced under reduced pressure. It was concentrated to dryness. Crude materials have low solubility in organic solvents. The residue was triturated with H ₂ O overnight, filtered and dried under high vacuum to give the title compound (43 mg, 33%).

The following compounds were prepared via amidation, as described for Example 12, Step 1, starting from the appropriate corresponding commercially available acids in Step 1.

Example 14: 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl) Preparation of indoline-6-carboxamide

Step 1: 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline -6-carboxamide

Imidazo[1,2-a]pyridine-3-carboxylic acid (0.012g, 0.072mmol) and HATU (0.030g, 0.079mmol) were dissolved in a 3:1 solution of anhydrous DCM (3ml) and DMF (1.000ml). , then N-ethyl-N-isopropylpropan-2-amine (0.027ml, 0.158mmol) was added in one portion. The solution was stirred at room temperature for 10 minutes, then Intermediate 25 (0.03 g, 0.072 mmol) was stirred in one portion. Stirring was maintained at room temperature for 16 h. After diluting with DCM (10 mL), the mixture was washed with sat NH ₄ Cl (10 mL), sat NaHCO ₃ (10 mL) and brine (10 mL). The organic phase was separated, dried _{over Na2SO4} , filtered and concentrated to dryness. The crude material was purified by reverse phase chromatography eluting with H ₂ O/MeCNH/HCO ₂ H (95:5:0.1 to 5:95:0.1) to give the title compound as the formate salt (9 mg, 22%). Obtained.

The following compounds were prepared via amidation using TBTU as the coupling agent as described for Example 14, Step 1, starting from the appropriate corresponding commercially available acids in Step 1. did.

Example 16: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-( Preparation of trifluoromethyl)benzamide

Step 1: tert-butyl 6-nitroindoline-1-carboxylate - intermediate 26

A flask was charged with BOC-anhydride (26.6 g, 122 mmol), 6-nitroindoline (20 g, 122 mmol), DMAP (1.5 g, 12.18 mmol), TEA (51 ml, 365 mmol), and DCM (244 ml). The reaction mixture was stirred at rt overnight. The solvent was stirred under vacuum. Extraction was performed with DCM. The solvent was removed once more. The crude product was purified by FCC eluting with hexane/ethyl acetate (9:1) to give the title compound (29g, 90%).

¹ H NMR (300 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.84 (dd, J = 8.2, 2.3 Hz, 1H), 7.49 - 7.40 (m, 1H), 4.01 (dd, J = 9.2, 8.2 Hz, 2H), 3.19 (t, J = 8.7 Hz, 2H), 1.54 (s, 9H).

Step 2: tert-butyl 6-aminoindoline-1-carboxylate - intermediate 27

Intermediate 26 (29.13 g, 110 mmol) was placed in a three-necked round button. Air was evacuated using a water pump and purged with Ar - the process was repeated three times. Then 10 wt.% palladium on carbon (2.91 g, 27.3 mmol) and ethyl acetate (551 ml) were added. The reaction mixture was purged with argon, removed using a water pump, and then purged with _H2 . The mixture was stirred at rt under hydrogen atmosphere overnight. The reaction mixture was filtered through a pad of Celite and concentrated to give the title compound (27g, 100%).

¹ H NMR (300 MHz, DMSO-d6) δ 7.05 (s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.13 (dd, J = 7.9, 2.1 Hz, 1H), 4.92 (d, J = 6.6 Hz, 2H), 3.82 (dd, J = 9.2, 7.9 Hz, 2H), 2.86 (t, J = 8.5 Hz, 2H), 1.50 (s, 9H).

Step 3: tert-butyl 6-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamido)indoline-1-carboxylate-intermediate 28

Intermediate 27 (6.45g, 21.34mmol) was placed in a flask, then HATU (16.23g, 42.7mmol), DIPEA (14.91ml, 85mmol), DMF (53.4ml) and dichloromethane (160ml) were added. The reaction mixture was stirred at rt for 30 min. Then tert-butyl 6-aminoindoline-1-carboxylate (5g, 21.34mmol) was added. Stirring was continued overnight. Extractions with water and DCM were performed. The organic phase was removed under reduced pressure. The crude product was purified by FCC eluting with hexane/ethyl acetate (9:1) to give the title compound (10.4g, 92%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.40 (s, 1H), 9.32 (s, 1H), 8.24 (d, J = 17.0 Hz, 2H), 8.15 (d, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.18 (d, J = 8.0 Hz, 1H), 3.94 (t, J = 8.5 Hz, 2H), 3.78 (s, 2H), 3.05 (t, J = 8.6 Hz, 2H), 2.70 (s, 3H), 2.40 (s, 8H), 1.52 (s, 9H).

Step 4: N-(indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide-Intermediate 29

Intermediate 28 (1.938g, 3.74mmol) was dissolved in DCM (37.4ml) and TFA (2.59ml, 33.6mmol) was added. The reaction mixture was stirred at rt overnight. The mixture was washed with sat NaHCO ₃ and brine (10 mL). The organic phase was separated, dried _{over Na2SO4} , filtered and concentrated to dryness. The crude material was purified by FCC eluting with DCM/MeOH (95:5). The pure fractions were washed with water, brine and 5% citric acid and finally the organic phase was dried over Na ₂ SO ₄ and evaporated under vacuum to give the title compound (770 mg, 48%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.16 (s, 1H), 8.14 (d, J = 6.8 Hz, 2H), 7.83 (s, 1H), 7.04 (d, J = 1.9 Hz, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.92 - 6.82 (m, 1H), 5.61 (s, 1H), 3.63 (s, 2H), 3.48 - 3.39 (m, 2H), 2.88 (t, J = 8.4 Hz, 2H), 2.37 (d, J = 22.8 Hz, 8H), 2.16 (s, 3H).

Step 5: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(tri Fluoromethyl)benzamide (Example 16)

Imidazo[1,2-a]pyridine-3-carboxylic acid (0.012g, 0.072mmol) and HATU (0.030g, 0.079mmol) were dissolved in a 3:1 solution of anhydrous DCM/DMF (5ml/1ml) and then To this, N-ethyl-N-isopropylpropan-2-amine (0.027ml, 0.158mmol) was added in one portion. The solution was stirred at room temperature for 10 minutes, then intermediate 29 (0.03 g, 0.072 mmol) was added in one portion. Stirring was maintained at room temperature for 16 h. The mixture was diluted with DCM (10 mL) and then washed with sat NH ₄ Cl (10 mL), sat NaHCO ₃ (10 mL) and brine (10 mL). The organic phase was separated, dried _{over Na2SO4} , filtered and concentrated to dryness. The crude material was purified by reverse phase column chromatography eluting with H ₂ O/MeCNH/HCO ₂ H (95:5:0.1 to 5:95:0.1) to give the title compound as the formate salt (31 mg, 71%). Obtained.

Example 17: N-(1-(benzo[d]thiazol-6-ylmethyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl) Preparation of benzamide

Intermediate 29 (0.1 g, 0.239 mmol) was dissolved in anhydrous DCM (2.4 ml), then benzo[d]thiazole-6-carbaldehyde (0.039 g, 0.239 mmol) was added, followed by AcOH (0.027 ml). , 0.478 mmol) was added. The reaction mixture was stirred at rt for 30 min. Then NaBH3CN (0.023g, 0.35) was added and the reaction mixture was stirred at rt overnight. The mixture was quenched by adding a sat.aq. solution of _NaHCO3 . Phase separation was performed and the aqueous phase was washed with DCM (x2). The organic phase was collected, dried over Na ₂ SO ₄ and the solvent was removed under vacuum. The crude material was purified by column chromatography eluting with DCM/MeOH (9:1) and preparative HPLC eluting with ACN, H ₂ O + 0.05% NH ₃ to give the title compound (20 mg, 15%). Obtained.

The following compounds were prepared via reductive amination using STAB as the reducing agent as described for Example 17, Step 1, starting from the appropriate corresponding commercially available aldehydes in Step 1. did.

Example 19: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-( Preparation of trifluoromethyl)benzamide

Step 1: tert-butyl 6-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamido)indoline-1-carboxylate-intermediate 30

3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzoic acid (1.15 g, 4.27 mmol), tert-butyl 6-aminoindoline-1-carboxylate (1.0 g, 4.27 mmol), HATU (4.87 g, 12.80 mmol), DIPEA (4.47 ml, 25.6 mmol) were placed in a flask, then DMF (0.907 ml) and DCM (2.721 ml) were added. The reaction mixture was stirred at rt overnight.

Extraction was performed with water and DCM. The solvent was dried over _Na2SO4 and removed under reduced pressure _. The crude material was purified by FCC eluting with hexane/ethyl acetate (1:1) to give the title compound (2.2g, 90%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.52 (s, 1H), 9.55 (s, 1H), 8.58 (s, 1H), 8.43 (d, J = 8.1 Hz, 2H), 8.15 (s, 2H) ), 7.21 (d, J = 8.0 Hz, 1H), 4.01 - 3.90 (m, 2H), 3.06 (t, J = 8.5 Hz, 2H), 2.36 (d, J = 1.2 Hz, 3H), 1.52 (s , 9H).

Step 2: N-(indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)benzamide - intermediate 31

Intermediate 30 (1.87g, 3.84mmol) was dissolved in DCM (38.4ml). Then TFA (2.67ml, 34.6mmol) was added. The reaction mixture was stirred at rt overnight. After washing with _NaHCO3 , the DCM was dried _{with Na2SO4} . Solvent was removed under reduced pressure. The crude product was purified by FCC eluting with DCM/MeOH (95:5). This was followed by extraction with water, brine and 5% citric acid to yield the title compound (1.09g, 53%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.40 (d, J = 1.5 Hz, 2H), 8.22 (s, 1H), 8.13 (s, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 7.8 Hz, 1H), 6.89 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 3.44 (d, J = 8.4 Hz, 2H), 2.89 (t, J = 8.4 Hz, 2H), 2.20 (s, 3H).

Step 3: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(tri Fluoromethyl)benzamide (Example 19)

Imidazo[1,2-a]pyridine-3-carboxylic acid (42.0mg, 0.259mmol), Intermediate 31 (100mg, 0.259mmol), TBTU (0.083g, 0.259mmol), TEA (72.1μl, 0.518mmol). It was placed in a vial and DMF (2.5ml) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was made basic with _{sat.sol.NaHCO3} . Extraction was performed with DCM. The solvent was dried over _Na2SO4 and removed under reduced pressure _. The crude product was purified by FCC eluting with DCM/MeOH (95:5) to give the title compound (98 mg, 69%).

The following compounds were prepared via amidation as described for steps 1-3 of Example 19 starting from the appropriate corresponding commercially available acids in step 3.

Example 22: N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-( Preparation of trifluoromethyl)benzamide

Step 1: N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(tri Fluoromethyl)benzamide (Example 22)

In a flask, intermediate 31 (100 mg, 0.259 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (38.1 mg, 0.259 mmol), magnesium sulfate (62.3 mg, 0.518 mmol) and DCM (2.6 ml) was loaded. Acetic acid (29.6 μl, 0.518 mmol) was added. The reaction mixture was stirred at rt for 2 h, then STAB (110 mg, 0.518 mmol) was added and the mixture was stirred overnight. Another portion of STAB (110 mg, 0.518 mmol) was added and stirring continued for another day. The mixture was quenched by adding _sat.NaHCO3 . Phase separation was performed and the aqueous phase was washed with DCM (x2). All organic phases were combined, dried _{over Na2SO4} , filtered and concentrated under reduced pressure. The crude material was purified by column chromatography eluting with DCM/MeOH (95:05) to give the title compound (75 mg, 53%).

The following compounds were prepared starting from the appropriate corresponding commercially available aldehydes via amidation as described for Example 22, Step 1, using NaBH ₃ CN as the reducing agent.

Example 24: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)- 5-(trifluoromethyl)phenyl)indoline-6-carboxamide

Step 1: Methyl 3-methylindoline-6-carboxylate-intermediate 32

Put methyl 3-methyl-1H-indole-6-carboxylate (1.5 g, 7.93 mmol), trifluoroacetic acid (4.86 ml, 63.1 mmol), and triethylsilane (5.06 ml, 31.7 mmol) into a flask, and add THF (30 ml). was added. The reaction mixture was stirred at 0°C overnight. A saturated solution of NaHCO ₃ was added and extraction was performed with DCM. The solvent was dried over _Na2SO4 and removed under reduced pressure _. The crude material was purified by FCC eluting with hexane/ethyl acetate (9:1) to give the title compound (950 mg, 62%).

¹ H NMR (300 MHz, DMSO-d6) δ 7.20 (dd, J = 7.6, 1.5 Hz, 1H), 7.11 (d, J = 7.6 Hz, 1H), 7.02 (d, J = 1.5 Hz, 1H), 5.72 (s, 1H), 3.79 (s, 3H), 3.63 (td, J = 8.9, 1.3 Hz, 1H), 3.31 - 3.23 (m, 1H), 3.02 (td, J = 8.6, 2.5 Hz, 1H) , 1.24 (d, J = 6.8 Hz, 3H).

Step 2: 1-(tert-butyl) 6-methyl 3-methylindoline-1,6-dicarboxylate-intermediate 33

Intermediate 32 (950 mg, 4.97 mmol), BOC-anhydride (1084 mg, 4.97 mmol), DMAP (61 mg, 0.497 mmol), triethylamine (2.077 ml, 14.90 mmol) were placed in a flask and DCM (50 ml) was added. The reaction mixture was stirred at rt overnight. Extraction was performed with DCM. The solvent was dried over _Na2SO4 and removed under reduced pressure _. The crude material was purified by FCC eluting with hexane:/ethyl acetate (4:1) to give the title compound (970 mg, 67%).

¹ H NMR (300 MHz, DMSO-d6) δ 8.26 (s, 1H), 7.60 (dd, J = 7.8, 1.6 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 4.13 (d, J = 12.5 Hz, 1H), 3.84 (s, 3H), 3.48 (d, J = 8.1 Hz, 2H), 1.52 (s, 9H), 1.28 (d, J = 6.5 Hz, 3H).

Step 3: 1-(tert-butoxycarbonyl)-3-methylindoline-6-carboxylic acid - intermediate 34

Intermediate 33 (0.95 g, 3.26 mmol), 1M lithium hydroxide (4.89 ml, 4.89 mmol), and MeOH (32.6 ml) were placed in a flask and stirred at rt overnight. Then, an additional 0.7 eq of 1M LiOH was added and stirring was continued until the next day. Solvent was removed under reduced pressure. The crude material as lithium salt was used in the next step without further purification (1.09 g, 100%). Alternatively, the chloride was removed by extraction with 5% aqueous citric acid to give the title compound in quantitative yield.

¹ H NMR (300 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.51 (dd, J = 7.6, 1.4 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 4.18 - 4.02 (m , 1H), 3.41 (t, J = 6.1 Hz, 2H), 1.51 (s, 9H), 1.24 (d, J = 6.5 Hz, 3H).

Step 4: tert-butyl 3-methyl-6-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate-intermediate 35

Intermediate 34 (1.5g, 5.41mmol), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (1.305g, 5.41mmol) in anhydrous DCM (54.1ml) and T3P (4.83 ml, 8.11 mmol) was added to a solution of DIPEA (5.67 ml, 32.5 mmol). The reaction was stirred at rt overnight. The reaction mixture was diluted with DCM (5ml) and water was added. Phase separation was performed and the organic phase was dried over Na ₂ SO ₄ and concentrated under vacuum. The crude material was purified by FCC eluting with DCM/MeOH (95:5) to give the title compound (1.7g, 61%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.28 (s, 1H), 8.20 (d, J = 1.4 Hz, 1H), 8.14 (s, 1H), 7.72 (s, 1H) ), 7.61 (dd, J = 7.8, 1.6 Hz, 1H), 7.52 - 7.46 (m, 1H), 7.41 (d, J = 7.8 Hz, 1H), 4.16 (d, J = 11.1 Hz, 1H), 3.50 (q, J = 8.7, 7.8 Hz, 2H), 2.18 (d, J = 1.0 Hz, 3H), 1.53 (s, 9H), 1.31 (d, J = 6.5 Hz, 3H).

The following intermediate 64 was prepared via amidation starting from intermediate 34 and changing the corresponding amine as described for step 4 of intermediate 35. Such procedures may involve minor changes. In some cases, if changes involve coupling agents (e.g. TCFH and 1-methylimidazole instead of T3P) or chromatographic purification conditions (e.g. prepHPLC or flash chromatography), report such changes in the table did.

Step 5: 3-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide-intermediate 36

Intermediate 35 (1.71g, 3.42mmol) was dissolved in DCM (34.2ml). Then TFA (2.369ml, 30.7mmol) was added. The reaction mixture was stirred at rt for 2 days. The reaction mixture was diluted with DCM (5ml) and a solution of _NaHCO3 in aq.Sat. was added. Then phase separation was performed and the organic phase was dried over Na ₂ SO ₄ and concentrated under vacuum. The crude product was purified by FCC eluting with DCM:MeOH (95:5) to give the title compound (1.07g, 76%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.33 - 8.26 (m, 1H), 8.22 - 8.15 (m, 2H), 7.70 (s, 1H), 7.48 (t, J = 1.3 Hz, 1H), 7.26 - 7.14 (m, 2H), 7.05 (d, J = 1.4 Hz, 1H), 3.66 (t, J = 8.9 Hz, 1H), 3.10 - 3.01 (m, 1H), 2.19 ( d, J = 1.0 Hz, 3H), 1.27 (d, J = 6.8 Hz, 3H).

The next intermediate 65 was prepared via acidic cleavage as described for intermediate 36 in step 5. Such procedures may include minor modifications. In some cases, where changes in chromatographic purification conditions (eg, replacing FCC with SCX) were included, such changes were reported in the table.

Step 6: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5 -(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 24)

In a flask, 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (36.7 mg, 0.250 mmol), intermediate 36 (100 mg, 0.250 mmol), acetic acid (28.6 μl, 0.499 mmol), magnesium sulfate (60.1 mg, 0.499 mmol) and DCM (2.5 ml). The reaction mixture was stirred at rt for 2 h. Then STAB (212 mg, 0.999 mmol) was added. Stirring was continued until the next day. The reaction mixture was diluted with DCM and a solution of NaHCO ₃ in aq.Sat. was added. Then phase separation was performed and the organic phase was dried over Na ₂ SO ₄ and concentrated under vacuum. The crude material was purified by FCC eluting with DCM:MeOH (9:1) to give the title compound (105 mg, 77%).

The following compounds were prepared via reductive amination as described for steps 1-6 of Example 24, starting from the appropriate corresponding commercially available aldehyde in step 6 and the corresponding amine in step 5. Prepared. In some cases, if they involved the addition of titanium (IV) isopropoxide or changes in chromatographic purification conditions (eg prepHPLC or flash chromatography), such changes were reported in the table.

Example 27: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoro Preparation of methyl)phenyl)indoline-6-carboxamide (single enantiomer)

Step 1: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) ) Preparation of phenyl)indoline-6-carboxamide (Example 27)

An amount of isolated racemic Example 26 (65 mg) was dissolved in EtOH to 5 mg/mL and then purified by chiral HPLC (SFC chiral separation) according to method 18. The fractions of the second eluted enantiomer were combined and evaporated to near dryness using a rotary evaporator. The solid obtained was transferred to a final container with the DCM removed under a stream of compressed air at 35°C, followed by storage in a vacuum oven at 35°C and 5 mbar, to give the title compound (23.10mg).

Example 28: 3-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(1H-pyrazolo[3,4-b] Preparation of pyridine-5-carbonyl)indoline-6-carboxamide

Intermediate 36 (0.1g, 0.250mmol), 1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (0.041g, 0.250mmol), TEA (69.6μl, 500mmol), TBTU (0.08g, 0.250mmol) ) was placed in a vial and DMF (2.5 ml) was added. The reaction mixture was stirred at rt overnight, then the temperature was raised to 80° C. and stirring continued until the next day. Extraction was performed with water and DCM. The organic phase was separated, dried over Na ₂ SO ₄ and removed under reduced pressure. The crude product was purified by preparative HPLC eluting with FCC DCM/MeOH (9:1) and ACN, H2O+0.05% _NH3 to give the title compound (15 mg, 11%).

The following compounds were prepared via amidation as described for Example 28, Step 1, starting from the appropriate corresponding commercially available acids in Step 1.

Example 30: Preparation of 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide

Step 1: tert-butyl 3-methyl-6-((3-(trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxylate-intermediate 37

1-(tert-butoxycarbonyl)-3-methylindoline-6-carboxylic acid (935 mg, 3.37 mmol), 3-(trifluoromethyl)aniline (543 mg, 3.37 mmol) and DIPEA ( To a solution of 3.53 ml, 20.23 mmol) was added T3P (3.01 ml, 5.06 mmol). The reaction was stirred at rt overnight. Water was added to the reaction mixture and the mixture was extracted with DCM (2x20ml). The organic solvent was dried over Na ₂ SO ₄ and removed under reduced pressure. The crude material was purified by FCC eluting with DCM/MeOH (95:5) to give the title compound (560 mg, 39%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.53 (s, 1H), 8.23 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.58 (dd, J = 7.7, 1.6 Hz, 2H ), 7.45 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 4.15 (d, J = 11.3 Hz, 1H), 3.54 - 3.44 (m, 2H), 1.53 (s , 9H), 1.30 (d, J = 6.5 Hz, 3H).

Step 2: 3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide-intermediate 38

Intermediate 37 (560 mg, 1.332 mmol) was dissolved in DCM (13.32 ml) and TFA (0.924 ml, 11.99 mmol) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with DCM and an aq.sat. solution of NaHCO ₃ was added. Phase separation was then performed and the organic phase was dried over Na ₂ SO ₄ and concentrated under vacuum. The crude material was purified by FCC eluting with DCM:MeOH (99:1) to give the title compound (375 mg, 86%).

¹ H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.25 (s, 1H), 8.03 (d, J = 8.2 Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.19 (dd, J = 7.6, 1.5 Hz, 1H), 7.15 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 1.4 Hz, 1H), 5.73 (s, 1H), 3.64 (td, J = 8.9, 1.3 Hz, 1H), 3.27 (d, J = 7.8 Hz, 1H), 3.04 (td, J = 8.6, 2.5 Hz, 1H), 1.26 (d , J = 6.8 Hz, 3H).

Step 3: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 30)

In a flask, 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (32.2 mg, 0.219 mmol), intermediate 38 (70 mg, 0.219 mmol), acetic acid (25.02 μl, 0.437 mmol), magnesium sulfate (52.6 mg, 0.437 mmol) and DCM (2185 μl). The reaction mixture was stirred at rt for 2 h. Then STAB (185 mg, 0.874 mmol) was added. Stirring was continued until the next day. The reaction was made basic with _NaHCO3 . Extraction was performed with DCM. Phase separation was then performed and the organic phase was dried over Na ₂ SO ₄ and concentrated under vacuum. The crude material was purified by FCC eluting with DCM/MeOH (95:5) to give the title compound (17 mg, 89%).

The following compounds were prepared via reductive amination as described for Example 30, Steps 1-3, starting from the appropriate corresponding commercially available aldehydes in Step 3.

Example 34: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (single Preparation of one enantiomer)

Step 1: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 34)

Chiral preparative SFC separation of 70 mg of racemic Example 30 gave the title compound as a single isomer. After preparative chiral separation, the combined fractions of the second eluted enantiomer were evaporated to dryness on a rotary evaporator to yield the title compound (11 mg, 15.6%).

Example 35: Preparation of 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide

Step 1: Methyl 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxylate-Intermediate 39

Methyl indoline-6-carboxylate (1g, 5.64mmol), 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (0.830g, 5.64mmol), acetic acid (0.646ml, 11.29mmol), magnesium sulfate ( 1.358g, 11.29mmol) was dissolved in DCM (56.4ml). The reaction mixture was stirred at rt for 2 h. Then STAB (2.392g, 11.29mmol) was added. Stirring was continued overnight. A Sat. solution of NaHCO ₃ was added and extraction was performed with DCM. The organic phase was dried over Na ₂ SO ₄ and removed under reduced pressure. The crude material was purified by FCC eluting with hexane/ethyl acetate (0-100%) to give the title compound (571 mg, 32.7%).

¹ H NMR (300 MHz, DMSO-d6) δ 13.64 (s, 1H), 8.54 (d, J = 2.1 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.13 (s, 1H), 7.27 (dd, J = 7.5, 1.4 Hz, 1H), 7.19 - 7.14 (m, 2H), 4.49 (s, 2H), 3.79 (s, 3H), 2.97 (t, J = 8.4 Hz, 2H).

Step 2: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 35)

A solution of 3-(trifluoromethyl)aniline (85 μl, 0.681 mmol) in anhydrous THF (1135 μl) was cooled to −78° C. under a flow of argon. Next, nBuLi (2.5M in hexanes) (272 μl, 0.681 mmol) was added. The mixture was stirred for 25 minutes and then a solution of intermediate 39 (70 mg, 0.227 mmol) in anhydrous THF (1135 μl) was added dropwise. The mixture was stirred at −78° C. for 0.5 h and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight. Water was added and extraction was performed with DCM. The organic phase was separated, dried over Na ₂ SO ₄ and removed under reduced pressure. The crude material was purified by FCC eluting with DCM/MeOH (95:5) to give the title compound (77.4 mg, 77%).

The following compounds were prepared via transamidation as described for Example 35, Steps 1-2, starting from the appropriate corresponding commercially available amine in Step 2.

Example 41: Preparation of N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide

Step 1: Methyl 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylate-Intermediate 40

Ethyl indoline-6-carboxylate hydrochloride (0.5 g, 2.340 mmol), imidazo[1,2-a]pyrazine-3-carbaldehyde (0.344 g, 2.340 mmol) and magnesium sulfate (0.563 g, 4.68 mmol) in argon I put it in a flask at the bottom. Anhydrous DCM (23.40ml) was added followed by AcOH (0.268ml, 4.68mmol). The reaction mixture was stirred at RT for 2 h. Then STAB (1.736g, 8.19mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and a 10% aqueous solution of NaHSO ₃ was added. This mixture was stirred for 20 minutes and phase separation was performed. The organic phase was washed three times with a 10% aqua solution of NaHSO ₃ to remove aldehyde residues. The organic phase was dried _{over Na2SO4} , filtered and concentrated under vacuum. The crude product was purified by FCC eluting with DCM/MeOH (1:0 to 1:1) to give the title compound (0.319g, 44.2%).

¹ H NMR (300 MHz, DMSO-d6) δ 9.08 (d, J = 1.5 Hz, 1H), 8.46 (dd, J = 4.7, 1.5 Hz, 1H), 7.94 (d, J = 4.7 Hz, 1H), 7.81 (s, 1H), 7.33 (d, J = 7.1 Hz, 2H), 7.22 - 7.16 (m, 1H), 4.76 (s, 2H), 3.82 (s, 3H), 3.22 (t, J = 8.3 Hz , 2H), 2.92 (t, J = 8.3 Hz, 2H).

Step 2: N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide (Example 41)

A solution of 3-fluoro-5-(trifluoromethyl)aniline (0.095ml, 0.730mmol) in anhydrous THF (1.216ml) was cooled to -78°C. Then nBuLi (2.5M in hexanes) (0.243ml, 0.608mmol) was added. The mixture was stirred for 25 minutes and then a solution of intermediate 40 (0.075g, 0.243mmol) in anhydrous THF (1.2ml) was added dropwise. The mixture was stirred at -78°C and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by preparative HPLC eluting with ACN, _H2O +0.05% _NH3 to give the title compound (0.061 g, 55% yield).

The following compounds were prepared via transamidation as described for Example 41, Steps 1-2, starting from the appropriate corresponding commercially available amine in Step 2.

Example 47: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-[4-(oxetan-3-ylmethoxy)-3-(trifluoromethyl)phenyl]indoline-6-carboxamide

Step 1: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylic acid - intermediate 41

Intermediate 40 (68 mg, 0.21 mmol) and NaOH 1N (0.6 ml) were stirred at rt for 2 h. The mixture was concentrated under reduced pressure. The residue was washed with water, filtered and dried under vacuum to give the title compound (65mg, 100%).

Step 2: 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-[4-(oxetan-3-ylmethoxy)-3-(trifluoromethyl)phenyl]indoline-6-carboxamide (implemented) Example 47)

To a mixture of intermediate 41 (65 mg, 0.221 mmol) and HATU (100.8 mg, 0.26) in DMF (0.6 ml) was added N,N-diisopropylethylamine (85.68 mg, 129.2 mmol). The reaction mixture was stirred at room temperature for 15 minutes and intermediate 16 (55 mg, 0.221 mmol) was added. The reaction mixture was stirred at room temperature and concentrated until LCMS showed consumption of starting material. Water and ethyl acetate were added to the reaction mixture. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified by reverse phase preparative _HPLC eluting with ACN/ _H2O (10mM _NH4CO3 ) to give the title compound (15.28mg, 13.1%).

The following compounds were prepared via amidation as described for Example 47, Steps 1-2, starting from the appropriate corresponding amine in Step 2.

Example 55: Preparation of 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide

Step 1: Methyl 1-(imidazo[1,2-a]pyridin-3-ylmethyl)indoline-6-carboxylate-Intermediate 42

Methyl indoline-6-carboxylate (1g, 5.64mmol), imidazo[1,2-a]pyridine-3-carbaldehyde (0.825g, 5.64mmol), acetic acid (0.646ml, 11.29mmol), magnesium sulfate (1.358g, 11.29 mmol) and DCM (56.4 ml) were placed in a flask and the reaction mixture was stirred at rt for 2 h, then STAB (2.392 g, 11.29 mmol) was added. Stirring was continued the next day. A saturated solution of _NaHCO3 was added. Extraction was performed with DCM. Solvent was removed under reduced pressure. The crude material was purified by FCC eluting with DCM/MeOH 95.5 to give the title compound (760 mg, 43%).

¹ H NMR (300 MHz, DMSO-d6) δ 8.36 (dt, J = 6.9, 1.2 Hz, 1H), 7.60 (dt, J = 9.1, 1.1 Hz, 1H), 7.56 (s, 1H), 7.35 (d , J = 1.4 Hz, 1H), 7.34 - 7.24 (m, 2H), 7.18 (d, J = 7.5 Hz, 1H), 6.96 (td, J = 6.8, 1.2 Hz, 1H), 4.69 (s, 2H) , 3.82 (s, 3H), 3.20 (t, J = 8.3 Hz, 2H), 2.91 (t, J = 8.3 Hz, 2H).

Step 2: 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide (Example 55)

A solution of 3-(trifluoromethoxy)aniline (121 mg, 0.683 mmol) in anhydrous THF (1139 μl) was cooled to -78°C. Next, nBuLi (2.5M in hexanes) (228 μl, 0.569 mmol) was added. The mixture was stirred for 25 minutes and then a solution of intermediate 42 (70 mg, 0.228 mmol) in anhydrous THF (1139 μl) was added dropwise. The mixture was stirred at -78°C and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight. Water and DCM were added to the reaction mixture. The two phases were separated and the aqueous phase was extracted once more with DCM. The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude material was purified by FCC eluting with DCM/MeOH (95:5) to give the title compound (87 mg, 84%).

The following compounds were prepared via transamidation as described for Example 55, Steps 1-2, starting from the appropriate corresponding commercially available amine in Step 2.

Example 60: Preparation of 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide

Step 1: Methyl 1-((1H-benzo[d]imidazol-5-yl)methyl)indoline-6-carboxylate-Intermediate 43

Methyl indoline-6-carboxylate hydrochloride (1.5 g, 7.02 mmol), 1H-benzo[d]imidazole-5-carbaldehyde (1.026 g, 7.02 mmol) and magnesium sulfate (1.690 g, 14.04 mmol) were dissolved under argon. I put it in a flask. Anhydrous DCM (46.8ml) was added followed by AcOH (0.804ml, 14.04mmol). The reaction mixture was stirred at RT for 2 h. Then STAB (5.21 g, 24.57 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was diluted with DCM and a 10% aqua solution of NaHSO ₃ was added. This mixture was stirred for 20 minutes and phase separation was performed. The organic phase was washed three times with a 10% aqueous solution of _NaHSO3 . The organic phase was dried _{over Na2SO4} , filtered and concentrated under vacuum. The crude product was purified via flash column chromatography eluting with DCM/MeOH (1:0 to 1:1). The resulting solid was triturated with water to give the title compound (1.068 g, 49.5% yield).

¹ H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.54 (d, J = 1.5 Hz, 1H), 7.23 (td, J = 7.9 , 1.5 Hz, 2H), 7.15 (d, J = 7.6 Hz, 1H), 7.07 (d, J = 1.4 Hz, 1H), 4.45 (s, 2H), 3.78 (s, 3H), 3.37 (t, 2H) ), 2.97 (t, J = 8.5 Hz, 2H).

Step 2: 1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 60)

A solution of 3-(trifluoromethyl)aniline (0.091ml, 0.732mmol) in anhydrous THF (1.220ml) was cooled to -78°C. Then nBuLi (2.5M in hexanes) (0.244ml, 0.610mmol) was added. The mixture was stirred for 25 minutes and then a solution of intermediate 43 (0.075g, 0.244mmol) in anhydrous THF (1.2ml) was added dropwise. The mixture was stirred at -78°C and slowly warmed to room temperature. The reaction mixture was stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture. The two phases were separated and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The crude product was purified via preparative HPLC eluting with ACN, _H2O +0.05% _NH3 to give the title compound (0.044g, 41.3% yield).

The following compounds were prepared via transamidation as described for Example 60, Steps 1-2, starting from the appropriate corresponding commercially available amine in Step 2.

Example 63: Preparation of 1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide

Step 1: 1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 63)

Pyrazolo[1,5- a] Titanium(IV) isopropoxide ( 139 mg, 0.489) was added and the mixture was refluxed for 2 h. The reaction was cooled to room temperature, NaBH ₃ CN (26 mg, 0.407 mmol) was added and stirring was continued at room temperature overnight. The reaction was quenched with water, filtered through Celite, and concentrated under vacuum. The residue was purified by reverse phase preparative HPLC eluting with ACN/H ₂ O (0.1% FA) to give the title compound (15 mg, 39%).

Example 64: 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoro Preparation of methyl)phenyl)indoline-6-carboxamide

Step 1: Methyl 3-acetyl-1H indole-6-carboxylate - intermediate 66

To a suspension of aluminum chloride (9.13 g, 68.5 mmol, 2.40 eq) and acetyl chloride (2.4 mL, 34.3 mmol, 1.20 eq) in DCM (100.00 mL) was added methyl indole-6-carboxylate (5.00 g, 28.5 mmol, 1.00eq) was added and the mixture was stirred at room temperature for 1 h. The mixture was placed on ice and extracted with ethyl acetate (x3) (filtration through Celite required). The organic extracts were combined, washed with brine and dried (Na ₂ SO ₄ ). The solvent was evaporated and the residue was triturated under ether and filtered to give the title compound (1.19g, 18%).

LCMS (Method 21 Report) t _R =1.04 min, m/z (M+1)= 218.1

Step 2: Methyl 3-ethylindoline-6-carboxylate-Intermediate 67

Triethylsilane (14 mL, 90.3 mmol, 18.0 eq) was added to a suspension of intermediate 66 (1.09 g, 5.02 mmol, 1.00 eq) in TFA (16 mL, 0.214 mol, 42.6 eq) and the mixture was stirred for 18 h. did. The mixture was concentrated under reduced pressure and the residue was partitioned between _NaHCO3 solution and DCM. The organic extracts were combined, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by FCC eluting with 50% EtOAC in cyclohexane to give the title compound (0.31 g, 29%).

¹ H NMR (400 MHz, CDCl3) d 7.43 (d, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.13 - 7.10 (m, 1H), 3.87 (s, 3H), 3.81 (s, 1H) ), 3.74 - 3.69 (m, 1H), 3.30 - 3.19 (m, 2H), 1.91 - 1.80 (m, 1H), 1.65 - 1.52 (m, 1H), 1.01 - 0.96 (m, 3H).

Step 3: Methyl 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylate intermediate-68

STAB (613 mg, 2.89 mmol, 2.00 eq) was combined with imidazo[1,2-a]pyrazine-3-carbaldehyde (266 mg, 1.81 mmol, 1.25 eq) in DCM (5.00 mL), intermediate 67 (297 mg, 1.45 mmol, 1.00eq), acetic acid (15uL) and magnesium sulfate (697mg, 5.79mmol, 4.00eq) and the mixture was stirred for 5h. The mixture was partitioned between _NaHCO3 solution and DCM (x3). The organic extracts were combined, dried (Na ₂ SO ₄ ) and evaporated. The residue was purified by FCC eluting with 1% MeOH in DCM to give the title compound (382 mg, 83%).

¹ H NMR (400 MHz, CDCl3) d 9.14 (s, 1H), 8.08 (d, J=4.6 Hz, 1H), 7.90 (d, J=4.6 Hz, 1H), 7.79 - 7.78 (m, 1H), 7.53 (d, J=7.6 Hz, 1H), 7.36 - 7.35 (m, 1H), 7.17 - 7.14 (m, 1H), 4.70 - 4.65 (m, 1H), 4.56 - 4.51 (m, 1H), 3.92 - 3.91 (s, 3H), 3.32 - 3.26 (m, 1H), 3.18 - 3.09 (m, 1H), 2.84 - 2.78 (m, 1H), 1.87 - 1.76 (m, 1H), 1.56 - 1.44 (m, 1H) ), 0.89 (t, J=7.4 Hz, 3H).

Step 4: Ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxylic acid - intermediate 69

LiOH (54 mg, 2.27 mmol, 2.00 eq) was added to a solution of intermediate 68 (382 mg, 1.14 mmol, 1.00 eq) in MeOH (2.00 mL) and water (0.50 mL) and the mixture was stirred at 50 °C for 64 h. did. The mixture was cooled to room temperature and HCl (1M; 2.27ml, 2.27mmol) was added. The reaction mixture was lyophilized. The resulting material was purified by FCC on silica gel (40 g cartridge, 0-100% DCM/MeOH 1:5 in DCM) to give the title compound (249 mg, 61%).

¹ H NMR (400 MHz, DMSO) d 9.38 (d, J=1.0 Hz, 1H), 8.69 - 8.67 (m, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 7.37 - 7.35 (m, 2H), 7.20 - 7.17 (m, 1H), 4.93 - 4.86 (m, 1H), 4.75 - 4.69 (m, 1H), 3.70 (br s, 1H), 3.42 (s, 1H) , 3.45 - 3.39 (m, 1H), 3.16 - 3.07 (m, 1H), 2.93 (t, J=8.1 Hz, 1H), 1.86 - 1.72 (m, 1H), 0.89 - 0.83 (m, 3H).

Step 5: 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl )phenyl)indoline-6-carboxamide-intermediate 70

Thionyl chloride (0.79 mL, 10.9 mmol, 50.0 eq) was added to intermediate 69 (70 mg, 0.217 mmol, 1.00 eq) and the mixture was stirred for 10 minutes. The mixture was dried under reduced pressure to obtain the intermediate acid chloride. The material was suspended in DCM (2 mL), 3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (105 mg, 0.434 mmol, 2.00 eq) was added, and the mixture was Stir for 20 minutes and leave overnight. The mixture was dried under reduced pressure and the residue was passed through an SCX-2 (10 g) cartridge, eluting with MeOH (30 mL) followed by 2M methanolic ammonia solution (50 mL). The eluates of the ammonia solution were combined and concentrated under reduced pressure. Purification by reverse phase preparative HPLC gave the title compound (7.96 mg, 6.7%).

¹ H NMR (400 MHz, DMSO) d 10.54 (s, 1H), 9.11 (d, J=1.5 Hz, 1H), 8.49 - 8.47 (m, 1H), 8.31 (d, J=1.8 Hz, 1H), 8.21 (d, J=1.4 Hz, 1H), 8.16 (s, 1H), 7.98 (d, J=4.6 Hz, 1H), 7.86 (s, 1H), 7.73 (s, 1H), 7.50 - 7.50 (m , 1H), 7.39 - 7.35 (m, 2H), 7.26 (d, J=7.4 Hz, 1H), 4.87 (d, J=15.3 Hz, 1H), 4.73 (d, J=15.3 Hz, 1H), 3.45 - 3.39 (m, 1H), 3.20 - 3.12 (m, 1H), 2.98 - 2.93 (m, 1H), 2.19 (s, 3H), 1.83 - 1.76 (m, 1H), 1.53 - 1.45 (m, 1H) , 0.91 - 0.85 (m, 3H).

Step 6: 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl )phenyl)indoline-6-carboxamide (Example 64)

Example 64 was performed on a racemic mixture of intermediate 70 using chiral preparative SFC purification (Waters/Thar SFC system, using a YMC Cellulose-C column, 40/60 IPA (0.1% diethylamine)/heptane isocratic run). , 1.0 ml/min) to obtain a single enantiomer (second elution).

Example 65: 3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoro Preparation of methyl)phenyl)indoline-6-carboxamide

Step 1: Ethyl 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)indoline-6-carboxylate acid - Intermediate 71

STAB (1108 mg, 5.23 mmol, 2.00 eq), 3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (527 mg, 3.27 mmol, 1.25 eq) in DCM (15.00 mL), ethyl It was added to a mixture of indoline-6-carboxylate (500 mg, 2.61 mmol, 1.00 eq), acetic acid (15 uL) and magnesium sulfate (1259 mg, 10.5 mmol, 4.00 eq) and the mixture was stirred at room temperature for 5 h. The mixture was partitioned between _NaHCO3 solution and DCM (x3). The organic extracts were combined, dried (Na ₂ SO ₄ ) and evaporated. The residue was triturated under ether and filtered to give the title compound (785mg, 89%).

LCMS (Method 21) t _R =1.41 min, m/z (M+1)= 337.2

Step 2: 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)indoline-6-carboxylic acid - intermediate 72

NaOH (192 mg, 4.80 mmol, 2.13 eq) was added to a solution of intermediate 71 (758 mg, 2.25 mmol, 1.00 eq) in MeOH (10.00 mL) and water (0.50 mL) and the mixture was stirred at 50 °C for 64 h. did. The mixture was cooled to rt and 1M HCl (4.8 mL, 4.80 mmol, 2.13 eq) was added dropwise to obtain a solid precipitate, which was filtered and washed with acetone (4 mL) to give the title compound (652 mg, 94 %) was obtained.

LCMS (Method 21) t _R 0.77 min, m/z (M+1) =309.2

Step 3: 1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3 -(trifluoromethyl)phenyl)indoline-6-carboxamide (Example 65)

To a mixture of intermediate 72 (50 mg, 0.162 mmol) and HATU (74 mg, 0.194 mmol) in DMF (0.1 M concentration) was added N,N-diisopropylethylamine (84 μL, 0.480 mmol). The reaction mixture was stirred at room temperature for 15 minutes, then 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline (53 mg, 0.195 mmol eq) was added. The reaction mixture was applied to a 5 g Isolute SCX-II cartridge pretreated with MeOH, washed with MeOH, and then eluted with 2M NH3/MeOH. The 2M NH ₃ /MeOH eluate was concentrated under reduced pressure. Purification by reverse phase preparative HPLC (Xbridge Phenyl 19x150mm, 10μm 40-100% MeOH/ _H2O (10mM _NH4HCO3 ), 20mL/ _min , RT) gave the title compound (33.59mg, 36%).

The following compounds were prepared via amidation as described for Example 65, Steps 1-3, using previously synthesized amines in Step 3 or commercially available amines. Such procedures may involve minor changes. In some cases, if coupling agents (eg, TCFH and methylimidazole), solvents or chromatographic purification conditions involved changes, such changes were reported in the table.

Example 75: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoro Preparation of methyl)phenyl)indoline-6-carboxamide

Step 1: tert-butyl 6-((4-((4-methylpiperazin-1-yl)methyl)-3-trifluoromethyl)phenyl)carbamoyl)indoline-1-carboxamide-intermediate 73

1-tert-butoxycarbonylindoline-6-carboxylic acid (1.00 g, 3.80 mmol) and 4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)aniline in DMF (10 mL) (1.25 g, 4.56 mmol) was added 1-methylimidazole (1.1 mL, 13.3 mmol) and TCFH (1.60 g, 5.70 mmol). The reaction mixture was stirred at rt for 24 h. The mixture was partitioned between brine (3x10mL) and EtOAc (10mL). The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by FCC eluting with 10% 2M _NH3 /MeOH in DCM to give the title compound (2.22g, 100%).
LCMS (Method 21) t _R =1.72 min, m/z (M+1)= 519

The following intermediates were prepared via amidation as described for step 1 of intermediate 73 using the appropriate commercially available or previously synthesized amines. Such procedures may involve minor changes. In some cases, coupling agents (e.g., TCFH and 1-methylimidazole were replaced with HATU and DIPEA), solvents (DMF was replaced with ACN), or chromatographic purification conditions (e.g., prepHPLC or flash chromatography) If changes were included, such changes were reported in the table.

Step 2: N-((4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)carbamoyl)indoline-6-carboxamide (intermediate 80)

Trifluoroacetic acid (3.3 mL, 42.8 mmol) was added to a solution of intermediate 73 (2.22 g, 4.28 mmol) in DCM (15 mL) and the mixture was stirred for 4 h. The mixture was concentrated under reduced pressure and the residue was passed through an SCX-2 (25 g) cartridge, eluting with MeOH (30 mL) followed by 2M methanolic ammonia solution (50 mL). The ammonia solution was concentrated under reduced pressure to give a residue, which was triturated under ether and filtered to give the title compound (1.47g, 82%).

¹ H NMR (400 MHz, DMSO) δ 10.28 - 10.26 (m, 1H), 8.21 - 8.19 (m, 1H), 8.01 (dd, J=1.9, 8.5 Hz, 1H), 7.68 - 7.65 (m, 1H) , 7.16 - 7.15 (m, 2H), 7.03 (s, 1H), 5.75 (s, 1H), 3.55 (s, 2H), 3.48 (dt, J=1.4, 8.6 Hz, 2H), 3.00 - 2.94 (m , 2H), 2.38 - 2.33 (m, 8H), 2.16 - 2.15 (m, 3H)

The following intermediates were prepared by acidic cleavage as described for step 2 of intermediate 80. Such procedures may include minor modifications. In some cases, if changes in chromatographic purification conditions (eg, prepHPLC or flash chromatography) were included, such changes were reported in the table.

Step 3: 1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl )phenyl)indoline-6-carboxamide, Example 75

Sodium triacetoxyborohydride (50.4 mg, 0.238 mmol), 1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (22 mg, 0.149 mmol), intermediate 80 (50 mg, 0.119 mmol), acetic acid (0.0001 mmol, 7 μL eq) and MgSO ₄ (117.32 mg, 0.476 mmol) and the mixture was stirred at room temperature until LCMS indicated consumption of starting material. The mixture was partitioned between saturated NaHCO ₃ (aq) and DCM, then re-extracted with DCM. The organic extracts were combined, dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The crude product was purified by reverse phase HPLC (Xbridge Phenyl 19x150mm, 10um 40-100% MeOH/ _H2O ( _{10mM NH4CO3} ), 20ml/min, RT) to give the title compound (50mg, 76%). I got it.

The following compounds are prepared starting from the corresponding intermediates described in step 2 and the appropriate corresponding commercially available or synthesized carboxylic acids in step 3, as described for steps 1-3 of Example 75. Prepared via reductive amination using aldehyde. Changes were made in the use of reducing agents (e.g. STAB replaced with NaBH ₃ CN), solvents (DCM replaced with MeOH), titanium(IV) isopropoxide, or chromatographic purification conditions (e.g. prepHPLC or flash chromatography). If any, such changes were reported in the table.

Example 87: N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide Preparation of:

Intermediate 41 (40%, 100 mg, 0.136 mmol) was suspended in thionyl chloride (6.42 mmol, 0.46 mL) and the reaction mixture was stirred at 50° C. for 2 h. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was suspended in toluene and reconcentrated to obtain the intermediate acyl chloride.

To a solution of 5-tert-butyl-1-methyl-pyrazol-3-amine (31 mg, 0.204 mmol) in pyridine (0.1 M concentration) was added the acyl chloride. The reaction mixture was stirred at 40° C. until LCMS showed consumption of starting material. The reaction mixture was evaporated, dissolved in MeOH (1 mL) and loaded onto an SCX-2 (5 g) cartridge, which was washed with MeOH. The compound was eluted using methanolic ammonia (2M) and the basic solution was evaporated. Purified by reverse phase preparative HPLC Sunfire C18 19x150mm, 10um 20-80% acetonitrile/water (10mM NH ₄ HCO ₃ ), 20ml/min, RT and then lyophilized to give the title compound (3.3mg, 6%). Obtained.

Example 88: Preparation of -(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(6-trifluoromethyl)pyrimidin-4-yl)indoline-6-carboxamide

Thionyl chloride (0.40 mL, 5.44 mmol, 40.0 eq) was added to intermediate 41 and the mixture was stirred at room temperature for 15 minutes. The mixture was dried under reduced pressure and the residue was suspended in dry DCM (2.00 mL). In a separate flask, 1 M lithium bis(trimethylsilyl)amide in THF (0.30 mL, 0.299 mmol, 2.20 eq) was dissolved in 6-(trifluoromethyl)pyrimidine-4- in dry tetrahydrofuran (2.00 mL) at 78 °C. Added dropwise to a solution of amine (27 mg, 0.163 mmol, 1.20 eq) and stirred the mixture for 15 minutes, then added dropwise to a suspension of acid chloride at -78°C. The reaction mixture was warmed to room temperature and stirred for 1 h. The solvent was evaporated and the residue was dissolved in MeOH (1 mL) and passed through an SCX-2 (10 g) cartridge, eluting with MeOH (30 mL) followed by 2M methanolic ammonia solution (20 mL). The eluates of the ammonia solution were combined and concentrated under reduced pressure. The residue (113 mg) was dissolved in 9:1 DMSO:water (1.0 mL) and purified by reverse-phase preparative HPLC (Xbridge Phenyl 19x150 mm, 10 um 40-100% MeOH/H ₂ O (10 mM NH4CO3), 20 ml/min). The title compound (13.04 mg, 21.04%) was obtained.

Example 89: N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-1-[(3-morpholino-1H-pyrazolo[3,4-b Preparation of ]pyridin-5-yl)methyl]indoline-6-carboxamide

Step 1: 1-[(3-bromo-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl]-N-[4-[(4-methylpiperazin-1-yl)methyl]-3 -(trifluoromethyl)phenyl]indoline-6-carboxamide-intermediate 87

A solution of intermediate 54 (74 mg, 0.33 mmol, 1.1 eq) in DCM (0.1 M concentration) contains intermediate 80 (125 mg, 0.30 mmol, 1 eq), titanium(IV) isopropoxide (170.53 mg, 0.060 mmol). and acetic acid (63 μL, 0.90 mmol) were added. The reaction mixture was stirred at room temperature for 1 h. STAB (127.16 mg 0.6 mmol) was added and the reaction mixture was stirred at room temperature until LCMS showed consumption of starting material to yield intermediate 87 (180 mg, 0.229 mmol, 77%). Proceed to the next step without further purification.

LCMS (Method 22): t _R =1.69 min, m/z (M+1)= 628/630

Step 2: N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-1-[(3-morpholino-1H-pyrazolo[3,4-b] pyridin-5-yl)methyl]indoline-6-carboxamide (Example 75)

A solution of intermediate 87 (80%, 70 mg, 0.0891 mmol) and morpholine (0.0086 mL, 0.0980 mmol) in 1,4-dioxane (3.00 mL) was sparged with _N2 . 1M lithium bis(trimethylsilyl)amide (0.45 mL, 0.446 mmol) was added dropwise and the resulting solution was degassed, followed by the addition of RuPhos Pd G3 (7.5 mg, 8.91 μmol, 0.1000 eq). The mixture was capped and heated to 80° C. for 1 h. The sample was cooled to room temperature and quenched with _H2O (1 mL). The mixture was extracted with EtOAc (3x5mL) and the organic phases were combined, dried ( _MgSO4 ) and evaporated. The residue was purified by preparative HPLC (Sunfire C18 19x150mm, 10um 5-60% ACN/H ₂ O (0.1% FA), 20ml/min, RT). The resulting material was dissolved in 10% MeOH in DCM and applied to a 2g SCX cartridge. The cartridge was washed with 50:50 MeOH:DCM, then the product was eluted with 1N NH ₃ in MeOH (20 mL). The solvent was evaporated under high vacuum to give the title compound (12mg, 21%).

When L ₁ is -C(O)NH- or -NHC(O)-, a -C(O)CH2- linker is inserted between the indoline ring and the Hy group instead of the -C(O) or CH2- linker. Comparative new synthetic compound with

Example C1: 1-(2-(imidazo[1,2-a]pyridin-3-yl)acetyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(tri Fluoromethyl)phenyl)indoline-6-carboxamide

2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (0.042 g, 0.239 mmol) was dissolved in DMF (2.4 ml), then TBTU (0.077 g, 0.239 mmol), TEA (0.067 ml, 0.478 mmol) was added. The mixture was stirred at room temperature for 15 minutes, then intermediate 25 (0.1 g, 0.239 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (5ml) and water (5ml). The mixture was stirred at room temperature for 15 minutes, then the phases were separated and the organic phase was washed with brine ( _2x15ml ), dried over _Na2SO4 , filtered and concentrated to dryness under reduced pressure. The crude material was triturated with a mixture of pentane and DCM (97/3). The residue was purified by preparative HPLC eluting with ACN+0.1% _NH3 , _H2O +0.1% _NH3 to give the title compound (26mg, 19%).

Example C2: N-(1-(2-(imidazo[1,2-a]pyridin-3-yl)acetyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl )-5-(trifluoromethyl)benzamide

2-(imidazo[1,2-a]pyridin-3-yl)acetic acid (37.9 mg, 0.215 mmol), intermediate 29 (90 mg, 0.215 mmol) and TEA (0.060 ml, 0.430 mmol) were dissolved in DMF (0.2 ml). ) and DCM (0.6 ml) and then TBTU (69.1 mg, 0.215 mmol) was added. The reaction was carried out at RT for 16 h. The reaction mixture was diluted with DCM and then extracted with water (1x5mL) and brine (1x5mL). The aqueous phases were combined and extracted with DCM. The organic phases were combined, dried _{over Na2SO4} , filtered and concentrated to dryness under vacuum. The crude material was purified by FCC eluting with DCM/MeOH (100:0 to 80:20) to give the title compound (83 mg, 67%).

Pharmacological activity in vitro assay of compounds of the invention
Binding assay

DDR1 and DDR2 binding assays were performed using Life Technologies' LanthaScreen ^™ Europium Kinase Binding assay. A white 384-well OptiPlate (PerkinElmer) containing 20 nM or 10 nM kinase tracer 178 and 2 nM europium-conjugated anti-GST antibody (Life Technologies), respectively, in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI2, 1 mM EGTA, 0.01% BRIJ35). ), compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) for 1 h at room temperature. The ratio of fluorescence emission at 665 nm/615 nm after excitation at 340 nm was determined using a Tecan Spark 20M plate reader. IC50 values were determined in GraphPad Prism 7.0 software using a four-parameter model of log(inhibitor) versus response. The IC50 value was converted to Ki using the Cheng-Prusoff formula (Ki=IC50/(1+[Tracer]/Kd)).

DDR1 Cell-Based Assay Inhibition of DDR1 receptor activation by compounds was assessed using the PathHunter® U2OS DDR1 assay (Eurofins DiscoverX) according to the manufacturer's instructions. Briefly, U2OS-DDR1 cells were seeded in white 384-well plates at a density of 5000 cells/well and incubated for 2 h at 37 °C and 5% _CO2 . Cells were then treated with similar concentrations of compounds and incubated for 30 minutes before being stimulated with 20 μg/ml of bovine type II collagen and incubated overnight at 37° C., 5% CO ₂ . PathHunter detection reagent was prepared according to the protocol provided by DiscoverX and this mix was added to each well at 20 μl/well. The plates were incubated in the dark at room temperature for 1 hour, and then the luminescence signal was acquired on a plate reader. Raw data were normalized to vehicle control (normalized to 0%) and positive control (normalized to 100%; cells treated with 20 μg/ml collagen II), and IC50 parameters were calculated using GraphPad Prism 8.0 software. Calculated using sigmoidal dose-response curve fitting with variable slope.

DDR2 Cell-Based Assay Inhibition of DDR2 phosphorylation by compounds was evaluated by phospho-ELISA assay using HEK293T-DDR2 recombinant cells. Briefly, HEK293T-DDR2 cells were seeded in poly-D-lysine coated 24-well plates at a density of 250.000 cells/well and incubated in DMEM+10% FBS at 37°C and 5% CO for 1.5 h. Afterwards, the medium was changed to serum-free DMEM and cells were incubated for 3 hours. Test compounds were then added at different concentrations 30 minutes before stimulation with 50 μg/ml bovine type II collagen for an additional 3 hours. For the DDR2 phospho-ELISA assay (DuoSet IC Human Phospho-DDR2; R&D Systems), protein extracts were obtained by adding 60 μl/well of lysis buffer prepared according to the manufacturer's instructions. Protein concentration in the samples was determined by BCA assay, and phospho-DDR2 levels were determined according to R&D Systems instructions. Raw data were normalized to maximum inhibition control (0% normalization) and positive control (100% normalization; cells treated with 20 μg/ml collagen II), and IC50 parameters were determined with GraphPad Prism 8.0 software. , calculated using sigmoidal dose-response curve fitting with variable slope.

The results for individual compounds are shown in Table 7, categorized in terms of binding affinity (Ki) for DDR1 and DDR2 receptors and potency (IC50) with respect to inhibitory activity for DDR1 and DDR2 receptors.

As can be seen, the compounds of Table 7, ie the compounds of the invention, exhibit good activity as antagonists of DDR1 and DDR2 receptors. Accordingly, the compounds of the invention may be used to treat fibrotic diseases such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. can be effectively used in the treatment of diseases, disorders or conditions associated with DDR receptors.

Comparative Examples The compounds of Examples C1 and C2 were tested in the same binding assay as described above.

As shown in Table 7, the compounds of the present invention have both binding affinities for DDR1 and DDR2 receptors expressed as Ki and inhibitory potencies expressed as IC50 for DDR1 and DDR2 receptors both below 80 nM, most of the For compounds it is less than 50 nM, even less than 25 nM. Conversely, as shown in Table 8, Comparative Examples C1 and C2 have binding affinities higher than 600 nM for the DDR1 receptor, 58000 binding affinities for C1, and C1 and C2 Both have a binding affinity of 58,000 for the DDR2 receptor. These data demonstrate that -CH2- or -CH2- or The presence of the -C(O)- linker is unexpectedly and surprisingly shown to determine the appropriate increase in inhibitory activity towards DDR1 and DDR2 receptors. In particular, a direct comparison of the compound of Example C1 of the present invention, which differs only in the linker between the indoline group and Hy, and the compounds of Examples 14 and 11 shows that -C(O)- and -CH2- linkers determine an unexpectedly significant increase in activity towards both DDR1 and DDR2 receptors.

Similarly, a direct comparison of the compound of Example C2 of the invention and the compound of Example 16, which differs only in the linker between the indoline group and the Hy, shows that the presence of the -C(O)- linker We highlight the unexpected and valuable increase in activity for both.

Claims (15)

Formula (I):
[In the formula,
R is H or -(C ₁ -C ₄ )alkyl;
L is selected from the group consisting of _-CH2- and -C(O)-;
L ₁ is selected from the group consisting of -C(O)NH- and -NHC(O)-;
Hy may be optionally substituted by one or more groups selected from -(C ₁ -C ₄ )alkyl, heterocycloalkyl and -(C ₁ -C ₄ )alkylene-NR _A R _B is a bicyclic heteroaryl, or Hy is a bicyclic semisaturated heteroaryl;
R _A is H or -(C ₁ -C ₄ )alkyl;
R _B is H or -(C ₁ -C ₄ )alkyl;
R ₁ is selected from the group consisting of Het and X, where
-Het is -(C ₁ -C ₄ )alkyl, -(C ₁ -C ₄ ) haloalkyl, -(C ₁ -C ₄ )alkylene-heterocycloalkyl-NR _A R _B , -(C ₁ -C _{4 )} ) _{alkylene - NR} optionally substituted by -C ₄ )alkyl;
-X is the expression:
(wherein R ₂ is selected from the group consisting of -O(C ₁ -C ₄ )haloalkyl, halogen atom and -(C ₁ -C ₄ )haloalkyl;
R ₃ is H or -O(C ₁ -C ₄ )alkyl, -C(O)NH-(C ₁ -C ₄ )alkylene-NR _A R _B , -C(O)-heterocyclo alkyl, wherein said heterocycloalkyl is optionally substituted by one or more -(C ₁ -C ₄ )alkyl, -O-heterocycloalkyl; , said heterocycloalkyl is one or more of -(C ₁ -C ₄ )alkyl, -O(C ₁ -C ₄ )alkylene-heterocycloalkyl, -(C ₁ -C ₄ )alkylene-NR _A R _B , heteroaryl optionally substituted by one or more -(C ₁ -C ₄ )alkyl, and optionally substituted by monocyclic heterocycloalkyl-(C ₁ -C ₄ )alkylene- wherein said heterocycloalkyl may be optionally substituted by one or more groups selected from -(C ₁ -C ₄ )alkyl and -NR _A R _B )
]
and pharmaceutically acceptable salts thereof. Formula (IA), where L ₁ is -C(O)NH-:
2. A compound of formula (I) according to claim 1, represented by: Formula (IA') where L is -C(O)-:
3. A compound of formula (IA) according to claim 2, represented by: 1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-(imidazo[1,2-a]pyridine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-(imidazo[1,2-a]pyrazine-3-carbonyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
3-Methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-(1H-pyrazolo[3,4-b]pyridine-5- carbonyl)indoline-6-carboxamide; and
1-(imidazo[1,2-a]pyrazine-3-carbonyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) 4. A compound of formula (IA') according to claim 3, selected from at least one of: indoline-6-carboxamide. Formula (IA''), where L is -CH ₂ -:
3. A compound of formula (IA) according to claim 2, represented by: 1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl ) indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6 -carboxamide;
1-(isoquinolin-7-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl ) indoline-6-carboxamide;
N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5 -yl)methyl)indoline-6-carboxamide;
1-((1H-indazol-5-yl)methyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl ) indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(tri Fluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) Indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) Indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) Indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazole-3 -yl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)-1-phenyl-1H-pyrazol-5-yl)indoline-6- carboxamide;
N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)indoline- 6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(4-methoxy-3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(4-((tetrahydrofuran-3-yl)oxy)-3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(morpholinomethyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
N-(3-((dimethylamino)methyl)-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide ;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(4-((1-methylpiperidin-4-yl)oxy)-3-(trifluoromethyl)phenyl)indoline-6- carboxamide;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide;
N-(3-fluoro-5-(trifluoromethoxy)phenyl)-1-(imidazo[1,2-a]pyridin-3-ylmethyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyridin-3-ylmethyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)indoline- 6-carboxamide;
N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(imidazo[1,2-a]pyridin-3-ylmethyl)indoline-6-carboxamide;
1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-(trifluoromethoxy)phenyl)indoline-6-carboxamide;
1-((1H-benzo[d]imidazol-5-yl)methyl)-N-(3-fluoro-5-(trifluoromethyl)phenyl)indoline-6-carboxamide;
1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide;
3-ethyl-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) Indoline-6-carboxamide;
1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(tri Fluoromethyl)phenyl)indoline-6-carboxamide;
1-((3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl)indoline -6-carboxamide;
N-(5-(tert-butyl)isoxazol-3-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide;
1-((3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-((4-methylpiperazin-1-yl)methyl)-5-(tri Fluoromethyl)phenyl)indoline-6-carboxamide;
N-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline -6-carboxamide;
1-((3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-(pyrrolidin-1-ylmethyl)-3-(trifluoromethyl)phenyl)indoline -6-carboxamide;
1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide;
(R)-N-(3-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-5-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3, 4-b]pyridin-5-yl)methyl)indoline-6-carboxamide;
N-(3-((2-(dimethylamino)ethyl)carbamoyl)-5-(trifluoromethyl)phenyl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridine-5- yl)methyl)indoline-6-carboxamide;
1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(4-methylpiperazine-1-carbonyl)-5-(trifluoromethyl) phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl ) indoline-6-carboxamide;
N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1-(pyrazolo[1,5-a]pyrimidin-6-ylmethyl)indoline-6- carboxamide;
1-((2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3- (trifluoromethyl)phenyl)indoline-6-carboxamide;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(tert-butyl)isoxazol-5-yl)indoline-6-carboxamide;
N-(3-(tert-butyl)isoxazol-5-yl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide;
N-(3-(tert-butyl)isoxazol-5-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide;
1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(2-((4-methylpiperazin-1-yl)methyl)-6-(tri fluoromethyl)pyridin-4-yl)indoline-6-carboxamide;
N-(2-((dimethylamino)methyl)-6-(trifluoromethyl)pyridin-4-yl)-1-((3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl )methyl)indoline-6-carboxamide;
1-((3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(5-(trifluoromethyl)pyridin-3-yl)indoline -6-carboxamide;
(R)-N-(2-((3-(dimethylamino)pyrrolidin-1-yl)methyl)-6-(trifluoromethyl)pyridin-4-yl)-1-((3-methyl-1H- Pyrazolo[3,4-b]pyridin-5-yl)methyl)indoline-6-carboxamide;
1-((3-Methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-N-(3-(2-(pyrrolidin-1-yl)ethoxy)-5-(trifluoro Methyl)phenyl)indoline-6-carboxamide;
N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1-(pyrazolo[1,5-a]pyrazin-3-ylmethyl)indoline-6- carboxamide;
N-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indoline-6-carboxamide;
1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-N-(6-(trifluoromethyl)pyrimidin-4-yl)indoline-6-carboxamide;
N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-1-((3-morpholino-1H-pyrazolo[3,4-b]pyridine-5 -yl)methyl)indoline-6-carboxamide;
1-((3-((dimethylamino)methyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)methyl)-N-(3-(trifluoromethyl)phenyl)indoline-6-carboxamide ;
1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-3-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide; and
selected from at least one of 1-(imidazo[1,2-a]pyrazin-3-ylmethyl)-3-methyl-N-(5-(trifluoromethyl)pyridin-3-yl)indoline-6-carboxamide; 6. The compound of (IA'') according to claim 5, wherein Formula (IB), where L ₁ is -NHC(O)-:
2. A compound of formula (I) according to claim 1, represented by: N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl) Benzamide;
N-(1-(benzo[d]thiazol-6-ylmethyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl)benzamide;
N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-((4-methylpiperazin-1-yl)methyl)-5-(trifluoromethyl) Benzamide;
N-(1-(imidazo[1,2-a]pyridine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) Benzamide;
N-(1-(imidazo[1,2-a]pyrazine-3-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) Benzamide;
N-(1-(1H-pyrazolo[3,4-b]pyridine-5-carbonyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoro methyl)benzamide;
N-(1-(imidazo[1,2-a]pyrazin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) Benzamide;
N-(1-(imidazo[1,2-a]pyridin-3-ylmethyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) Benzamide;
N-(1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indolin-6-yl)-3-(trifluoromethyl)benzamide; and
N-(1-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)indolin-6-yl)-3-(4-methyl-1H-imidazol-1-yl)-5- 8. The compound of formula (IB) according to claim 7, selected from at least one of: (trifluoromethyl)benzamide. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 8, together with one or more pharmaceutically acceptable carriers or excipients. 10. A pharmaceutical composition according to claim 9, for administration by inhalation. 11. A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutical composition according to claim 9 or 10 for use as a medicament. 12. A compound of formula (I) or a pharmaceutical composition for use according to claim 11 in the prevention and/or treatment of diseases, disorders or conditions associated with dysregulation of DDR. 13. A compound or pharmaceutical composition of formula (I) for use according to claim 11 or 12 in the prevention and/or condition of fibrosis and/or diseases, disorders or conditions in which fibrosis is involved. In the prevention and/or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), liver fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. , a compound of formula (I) or a pharmaceutical composition for use according to claim 13. 15. A compound of formula (I) or a pharmaceutical composition for use according to claim 14 in the prevention and/or treatment of idiopathic pulmonary fibrosis (IPF).